Редактирование: CDK4 (раздел)

==Publications==

{{medline-entry
|title=Emerging Roles for the [i]INK4a/ARF[/i] ([i]CDKN2A[/i]) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32971832
|abstract=Besides its role as a cell cycle and proliferation regulator, the [i]INK4a/ARF[/i] ([i]CDKN2A[/i]) locus and its associated pathways are thought to play additional functions in the control of energy homeostasis. Genome-wide association studies in humans and rodents have revealed that single nucleotide polymorphisms in this locus are risk factors for obesity and related metabolic diseases including cardiovascular complications and type-2 diabetes (T2D). Recent studies showed that both p16 -[[CDK4]]-E2F1/pRB and p19 -P53 (p14  in humans) related pathways regulate adipose tissue (AT) physiology and adipocyte functions such as lipid storage, inflammation, oxidative activity, and cellular plasticity (browning). Targeting these metabolic pathways in AT emerged as a new putative therapy to alleviate the effects of obesity and prevent T2D. This review aims to provide an overview of the literature linking the [i]INK4a/ARF[/i] locus with AT functions, focusing on its mechanisms of action in the regulation of energy homeostasis.

|keywords=* adipogenesis
* inflammation
* insulin sensitivity
* obesity
* oxidative activity
* senescence
* type 2 diabetes
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563355
}}
{{medline-entry
|title=Guilu Erxian Glue () Inhibits Chemotherapy-Induced Bone Marrow Hematopoietic Stem Cell Senescence in Mice May via p16 -Rb Signaling Pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32915425
|abstract=To evaluate the effect of Guilu Erxian Glue (, GEG) on cyclophosphamide (CTX)-induced bone marrow hematopoietic stem cells (HSCs) senescence in mice and explore the underlying mechanism. The H  liver cancer ascites lump model was established in male Kunming mice by injecting intraperitoneally (i.p.) with 5 × 10 /mL H  cells per mouse. Fifty tumor-bearing mice were divided into the control, model, pifithrin-α, GEG, and GEG pifithrin-α groups using a random number table, 10 mice in each group. CTX (100 mg/kg i.p.) was administrated to mice from day 1 to day 3 (d1-d3) continuously except for the control group. The mice in the pifithrin-α, GEG and GEG pifithrin-α groups were treated with pifithrin-α (2.2 mg/(kg·d) i.p.) for 6 consecutive days (d4-d9), GEG (9.5 g/(kg·d) i.p.) for 9 consecutive days (d1-d9), and GEG plus pifithrin-α, respectively. HSCs were collected after 9-d drug treatment. The anti-aging effect of GEG was studied by cell viability, cell cycle, and β -galactosidase (β -gal) assays. The mRNA and protein expressions of cyclin-dependent kinase 2 ([[CDK2]]), [[CDK4]], inhibitor of cyclin-dependent kinase 4a encoding the tumor suppressor protein p16 (p16 ), p21 , p53, and phosphorylated retinoblastoma (pRb) were evaluated by quantitative real-time reverse transcription-polymerase chain reaction and semi-quantitative Western blot, respectively. Compared with the model group, GEG increased cell viability as well as proliferation (P<0.05 or P<0.01) and reduced β -gal expression. Furthermore, GEG significantly decreased the expressions of p16 , p53 and p21  proteins, and increased the expressions of [[CDK2]], [[CDK4]] and pRb proteins compared with the model group (P<0.05 or P<0.01). GEG can alleviate CTX-induced HSCs senescence in mice, and the p16 -Rb signaling pathway might be the underlying mechanism.

|keywords=* Chinese medicine
* Guilu Erxian Glue
* bone marrow suppression
* hematopoietic stem cell senescence
* p16INK4a
|full-text-url=https://sci-hub.do/10.1007/s11655-020-3098-3
}}
{{medline-entry
|title=Hepatoprotective effects of hydroxysafflor yellow A in D-galactose-treated aging mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32454116
|abstract=Hydroxysafflor yellow A (HSYA) is an effective chemical component isolated from Chinese herb Carthamus tinctorius L. In present study, we aimed to evaluate the effects of HSYA on D-galactose- (D-gal-) induced aging in mice, and to elucidate the underlying mechanism. Male C57BL/6 mice were intraperitoneal injection of D-gal and HSYA for 8 weeks. The body weight gain, spleen and thymus coefficients were determined. Levels of super dismutase (SOD), catalase ([[CAT]]), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in serum and liver were measured using commercial kits. Pathological changes and the SA-β-Gal activity in liver tissues were detected by hematoxylin and eosin and SA-β-Gal staining. The expression levels of p16, [[CDK4]], [[CDK6]] and phosphorylation levels of Retinoblastoma (Rb) were detected by immunohistochemistry and western blot analysis. mRNA levels of genes regulated by p16-Rb pathway were determined by quantitative real-time PCR. In vivo, HSYA improved the aging changes including body weight, organ index and antioxidant status such as activities of SOD, [[CAT]], GSH-Px and MDA in D-gal treated aging mice. HSYA also dramatically attenuated pathologic changes of aging liver tissues induced by D-gal. Furthermore, HSYA significantly decreased the mRNA and protein level of cyclin-dependent kinase inhibitor p16, followed by increasing [[CDK4]]/6 protein expression and decreasing the phosphorylation of Retinoblastoma (pRb) which up-regulated the expression of downstream genes [[CCNE1]], [[CCNA2]], P107 and [[MCM4]]. Collectively, these data indicated that HSYA could ameliorate aging, especially hepatic replicative senescence resulting from D-gal, the mechanism could be associated with the suppression of p16-Rb pathway.

|keywords=* D-galactose
* Hydroxysafflor yellow A
* Oxidative stress
* Replicative senescence
* p16
|full-text-url=https://sci-hub.do/10.1016/j.ejphar.2020.173214
}}
{{medline-entry
|title=Astragaloside IV ameliorates radiation-induced senescence via antioxidative mechanism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32412100
|abstract=Ageing is a universal and gradual process of organ deterioration. Radiation induces oxidative stress in cells, which leads to genetic damage and affects cell growth, differentiation and senescence. Astragaloside (AS)-IV has antioxidative, anti-apoptotic and anti-inflammatory properties. To study the protective mechanism of AS-IV on radiation-induced brain cell senescence, we constructed a radiation-induced brain cell ageing model, using biochemical indicators, senescence-associated galactosidase (SA-β-gal) senescence staining, flow cytometry and Western blotting to analyse the AS-IV resistance mechanism to radiation-induced brain cell senescence. Radiation reduced superoxide dismutase (SOD) activity and expressions of cyclin-dependent kinase (CDK2), [[CDK4]], cyclin E and transcription factor [[E2F1]] proteins, and increased expressions of p21, p16, cyclin D and retinoblastoma (RB) proteins, malondialdehyde (MDA) activity, SA-β-gal-positive cells and cells stagnating in G1 phase. After treatment with AS-IV, the level of oxidative stress in cells significantly decreased and expression of proteins related to the cell cycle and ageing significantly changed. In addition, SA-β-gal-positive cells and cells arrested in G1 phase were significantly reduced. These data suggest that AS-IV can antagonize radiation-induced brain cells senescence; and its mechanism may be related to p53-p21 and p16-RB signalling pathways of ageing regulation.

|keywords=* cell signal pathway
* nerve cells
* radiation
* senescence
|full-text-url=https://sci-hub.do/10.1111/jphp.13284
}}
{{medline-entry
|title=Expression of p16 in nodular fasciitis: an implication for self-limited and inflammatory nature of the lesion.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31933915
|abstract=Nodular fasciitis (NF) is a self-limited tumorous lesion occurring in the upper as well as lower extremities. NF is composed of a proliferation of "primary culture"-like myofibroblastic cells with nuclear atypia and large nucleoli, thus mimicking sarcoma. NF harbors a promoter-swapping fusion gene containing the entire coding region of [i]USP6[/i] gene. Therefore, NF is a tumor with a fusion oncogene but self-limited. In order to explore why NF is self-limited, we examined whether myofibroblastic cells in NF express p16 protein, a gene product of [i]CDKN2A[/i] gene and an inhibitor of cyclin-dependent kinase 4 ([[CDK4]]) as well as one of the hallmarks of cellular senescence. We immunohistochemically demonstrated strong and diffuse expression of p16 in myofibroblastic cells in 11 out of 15 cases of NF, and strong but partial expression in the remaining 4 of the cases. We also showed that 15 out of 15 cases of NF were immunohistochemically negative or only showed focal and faint immunopositivity for [[CDK4]], murine double minute 2 (MDM2), and [[TP53]] proteins. Furthermore, there were no significant changes in the copy number of [i]CDKN2A, [[CDK4]][/i] and [i]MDM2[/i] genes, and no significant mutations in [i][[TP53]], [[RB1]],[/i] and [i]CDKN2A[/i] genes in 1 case of NF selected. These data suggest a possible involvement in cell cycle arrest and presumed cellular senescence by p16 in myofibroblastic cells in NF. This may explain the self-limited as well as inflammatory nature of NF as a senescence-associated secretory phenotype.

|keywords=* CDK4
* MDM2
* TP53
* nodular fasciitis
* p16
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945175
}}
{{medline-entry
|title=Anti-cell growth and anti-cancer stem cell activity of the [[CDK4]]/6 inhibitor palbociclib in breast cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31823286
|abstract=A cyclin-dependent kinase (CDK) 4/6 inhibitor, palbociclib, has been used to treat patients with estrogen receptor (ER)-positive ( ) and human epidermal growth factor receptor (HER) 2-negative (-) advanced breast cancer. To investigate the mechanisms underlying the antitumor activity of palbociclib, we conducted a preclinical study on the anti-cell growth and anti-cancer stem cell (CSC) activity of palbociclib in breast cancer cells. The effects of palbociclib on Rb phosphorylation, cell growth, cell cycle progression, apoptosis, cell senescence and the proportion of CSCs were investigated in five human breast cancer cell lines of different subtypes. To investigate the mechanisms of the anti-CSC activity of palbociclib, small-interfering RNAs for [[CDK4]] and/or [[CDK6]] were used. Palbociclib dose-dependently reduced Rb phosphorylation and cell growth in association with G1-S cell cycle blockade and the induction of cell senescence, but without increased apoptosis, in all breast cancer cell lines. The anti-cell growth activity of palbociclib widely differed among the cell lines. Palbociclib also dose-dependently reduced the CSC proportion measured by three different assays in four of five cell lines. The inhibition of [[CDK4]] expression, but not [[CDK6]] expression, reduced the increased proportion of putative CSCs induced by estradiol in ER ( )/HER2 (-) cell lines. These results suggest that palbociclib exhibits significant anti-cell growth and anti-CSC activity in not only ER ( ) breast cancer cell lines but also ER (-) cell lines. [[CDK4]] inhibition induced by palbociclib may be responsible for its anti-CSC activity.

|keywords=* Breast cancer
* CDK4
* Cancer stem cells
* Palbociclib
* Senescence
|full-text-url=https://sci-hub.do/10.1007/s12282-019-01035-5
}}
{{medline-entry
|title=Compromising the constitutive p16  expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31692039
|abstract=The Hsp90 chaperone has become the attractive pharmacological target to inhibit tumor cell proliferation. However, tumor cells can evolve with mechanisms to overcome Hsp90 inhibition. Using human neuroblastoma, we have investigated one such limitation. Here, we demonstrate that neuroblastoma cells overcome the interference of tumor suppressor p16  in cell proliferation, which is due to its latent interaction with [[CDK4]] and [[CDK6]]. Cells also displayed impedance to the pharmacological inhibition of cancer chaperone Hsp90 inhibition with respect to induced cytotoxicity. However, the p16  knockdown has triggered the activation of cyclin-[[CDK6]] axis and enhanced the cell proliferation. These cells are eventually sensitized to Hsp90 inhibition by activating the DNA damage response mediated through p53-p21  axis and G1 cell cycle exit. While both [[CDK4]] and [[CDK6]] have exhibited low affinity to p16  , [[CDK6]] has exhibited high affinity to Hsp90. Destabilizing the [[CDK6]] interaction with Hsp90 has prolonged G2/M cell cycle arrest fostering to premature cellular senescence. The senescence driven cells exhibited compromised metastatic potential both in vitro as well as in mice xenografts. Our study unravels that cancer cells can be adapted to the constitutive expression of tumor suppressors to overcome therapeutic interventions. Our findings display potential implication of Hsp90 inhibitors to overcome such adaptations.

|keywords=* 17AAG
* Hsp90
* cancer
* p16INK4a
* senescence
* tumor suppressor
|full-text-url=https://sci-hub.do/10.1002/jcb.29493
}}
{{medline-entry
|title=Induction of Senescence in Cancer Cells by a Novel Combination of Cucurbitacin B and Withanone: Molecular Mechanism and Therapeutic Potential.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31112603
|abstract=Cancer, an uncontrolled proliferation syndrome, is treated with synthetic chemotherapeutic drugs that are associated with severe adverse effects. Development and application of new natural compounds is warranted to deal with the exponentially increasing incidence of cancer worldwide. Keeping selective toxicity to cancer cells as a priority criterion, we developed a combination of Cucurbitacin B and Withanone, and analyzed its anticancer potential using non-small cell lung cancer cells. We demonstrate that the selective cytotoxicity of the combination, called CucWi-N, to cancer cells is mediated by induction of cellular senescence that was characterized by decrease in Lamin A/C, [[CDK2]], [[CDK4]], Cyclin D, Cyclin E, phosphorylated RB, mortalin and increase in p53 and [[CARF]] proteins. It compromised cancer cell migration that was mediated by decrease in mortalin, hnRNP-K, vascular endothelial growth factor, matrix metalloproteinase 2, and fibronectin. We provide in silico, molecular dynamics and experimental data to support that CucWi-N (i) possesses high capability to target mortalin-p53 interaction and hnRNP-K proteins, (ii) triggers replicative senescence and inhibits metastatic potential of the cancer cells, and (iii) inhibits tumor progression and metastasis in vivo. We propose that CucWi-N is a potential natural anticancer drug that warrants further mechanistic and clinical studies.

|keywords=* Anticancer
* Antimetastatic
* Cucurbitacin B
* Senescence
* Withanone
|full-text-url=https://sci-hub.do/10.1093/gerona/glz077
}}
{{medline-entry
|title=Ribosomal protein RPL22/eL22 regulates the cell cycle by acting as an inhibitor of the [[CDK4]]-cyclin D complex.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30874462
|abstract=Senescence is a tumor suppressor program characterized by a stable growth arrest while maintaining cell viability. Senescence-associated ribogenesis defects (SARD) have been shown to regulate senescence through the ability of the ribosomal protein S14 (RPS14 or uS11) to bind and inhibit the cyclin-dependent kinase 4 ([[CDK4]]). Here we report another ribosomal protein that binds and inhibits [[CDK4]] in senescent cells: L22 (RPL22 or eL22). Enforcing the expression of RPL22/eL22 is sufficient to induce an RB and p53-dependent cellular senescent phenotype in human fibroblasts. Mechanistically, RPL22/eL22 can interact with and inhibit [[CDK4]]-Cyclin D1 to decrease RB phosphorylation both in vitro and in cells. Briefly, we show that ribosome-free RPL22/eL22 causes a cell cycle arrest which could be relevant during situations of nucleolar stress such as cellular senescence or the response to cancer chemotherapy.
|mesh-terms=* Cell Cycle
* Cell Cycle Checkpoints
* Cell Line
* Cellular Senescence
* Cyclin D1
* Cyclin-Dependent Kinase 4
* HEK293 Cells
* Humans
* Phosphorylation
* RNA-Binding Proteins
* Retinoblastoma Protein
* Ribosomal Proteins
* Ribosomes
* Signal Transduction
* Tumor Suppressor Protein p53
|keywords=* CDK4
* RPL22/eL22
* RPS14/uS11
* Ribosome biogenesis
* cyclin D1
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464582
}}
{{medline-entry
|title=p16  deletion in cells of the intervertebral disc affects their matrix homeostasis and senescence associated secretory phenotype without altering onset of senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30811968
|abstract=Intervertebral disc degeneration is an important contributor to chronic low back and neck pain. Although many environmental and genetic factors are known to contribute to disc degeneration, age is still the most significant risk factor. Recent studies have shown that senescence may play a role in age-related disc degeneration and matrix catabolism in humans and mouse models. Clearance of p16 -positive senescent cells reduces the degenerative phenotype in many age-associated diseases. Whether p16  plays a functional role in intervertebral disc degeneration and senescence is unknown. We first characterized the senescence status of discs in young and old mice. Quantitative histology, gene expression and a novel p16  reporter mice showed an increase in p16 , p21 and IL-6, with a decrease in Ki67 with aging. Accordingly, we studied the spinal-phenotype of 18-month-old mice with conditional deletion of p16  in the disc driven by Acan-CreERT2 (cKO). The analyses of discs of cKO and age-matched control mice showed little change in cell morphology and tissue architecture. The cKO mice exhibited changes in functional attributes of aggrecan as well as in collagen composition of the intervertebral disc. While cKO discs exhibited a small decrease in TUNEL positive cells, lineage tracing experiments using ZsGreen reporter indicated that the overall changes in cell fate or numbers were minimal. The cKO mice maintained expression of NP-cell phenotypic markers [[CA3]], Krt19 and GLUT-1. Moreover, in cKO discs, levels of p19  and RB were higher without alterations in Ki67, γH2AX, [[CDK4]] and Lipofuscin deposition. Interestingly, the cKO discs showed lower levels of SASP markers, IL-1β, IL-6, MCP1 and TGF-β1. These results show that while, p16  is dispensable for induction and maintenance of senescence, conditional loss of p16  reduces apoptosis, limits the SASP phenotype and alters matrix homeostasis of disc cells.
|mesh-terms=* Aggrecans
* Aging
* Animals
* Cellular Senescence
* Collagen
* Cyclin-Dependent Kinase Inhibitor p16
* Disease Models, Animal
* Extracellular Matrix
* Gene Deletion
* Homeostasis
* Humans
* Intervertebral Disc Degeneration
* Mice
* Phenotype
|keywords=* Aggrecan
* Aging
* Extracellular matrix
* Ink4a
* Intervertebral disc degeneration
* Mouse models
* Nucleus pulposus
* SASP
* Senescence
* p16
* p19
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708504
}}
{{medline-entry
|title=Efficient immortalization of cells derived from critically endangered Tsushima leopard cat (Prionailurus bengalensis euptilurus) with expression of mutant [[CDK4]], Cyclin D1, and telomerase reverse transcriptase.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30225752
|abstract=Tsushima leopard cat is the subspecies of Amur cats, and it is classified as the most highest class of critically endangered animals. Although the protection activity is highly recognized, the number of animals is decreasing due to the human activity and invasion of domestic cats and infectious disease. In this study, we succeeded primary culture of normal fibroblasts derived from the Tsushima leopard cat (Prionailurus bengalensis euptilurus). Furthermore, we introduced the human derived mutant Cyclin Dependent Kinase 4, Cyclin D1, and telomere reverse transcriptase. We showed that the expression of these three genes efficiently immortalized cells derived from Tsushima leopard cat. Furthermore, we showed that the chromosome pattern of the established cells is identical with the original one. These data indicate that our method of immortalization is useful to establish cell lines from critically endangered cats, which potentially contributes to the re-generation of critically endangered animals from cultured cell with reproductive technique, such as somatic cloning.

|keywords=* Cellular senescence
* Endangered animals
* Immortalization
* Tsushima leopard cat
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269356
}}
{{medline-entry
|title=Effects of Fibronectin 1 on Cell Proliferation, Senescence and Apoptosis of Human Glioma Cells Through the PI3K/AKT Signaling Pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30048971
|abstract=The current study aimed to investigate the role by which fibronectin 1 ([[FN1]]) influences the cell cycle, senescence and apoptosis in human glioma cells through the PI3K/ AKT signaling pathway. Differentially expressed genes (DEGs) were identified based on gene expression data (GSE12657, GSE15824 and GSE45921 datasets) and probe annotation files from Gene Expression Omnibus. The DEGs were identified in connection with gene ontology (GO) enrichment analysis and with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The positive expression of the [[FN1]] protein was detected by immunohistochemistry. The glioma cell lines U251 and T98G were selected and assigned into blank, negative control (NC) and siRNA-[[FN1]] groups. A dual luciferase reporter gene assay was used to investigate the effects of [[FN1]] on transcriptional activity through the PI3K/AKT signaling pathway. An MTT assay was applied for the detection of cell proliferation, while flow cytometry was employed for cell cycle stage and cellular apoptosis detection. β-galactosidase staining was utilized to detect cellular senescence, a scratch test was applied to evaluate cell migration, and a transwell assay was used to analyze cell invasion. Western blotting and qRT-PCR methods were used to detect the protein and mRNA expression levels, respectively, of the [[FN1]] gene and the related genes in the PI3K/AKT pathway (PI3K, AKT and PTEN), the cell cycle (pRb, [[CDK4]] and Cyclin D1) and cell senescence (p16 and p21) among the collected tissues and cells. GSE12657 profiling revealed [[FN1]] to be the most upregulated gene in glioma. Regarding the GSE12657 and GSE15824 datasets, [[FN1]] gene expression was higher in glioma tissues than in normal tissues. GO enrichment analysis and KEGG pathway enrichment analysis indicated that [[FN1]] is involved in the synthesis of extracellular matrix (ECM) components and the PI3K/AKT signaling pathway. Verification was provided, indicating the role played by the [[FN1]] gene in the regulation of the PI3K/AKT signaling pathway, as silencing the [[FN1]] gene was found to inhibit cell proliferation, promote cell apoptosis and senescence, and reduce migration and invasion through the down-regulation of [[FN1]] gene expression and disruption of the PI3K-AKT signaling pathway. The findings of this study provide evidence highlighting the prominent role played by [[FN1]] in stimulating glioma growth, invasion, and survival through the activation of the PI3K/AKT signaling pathway.
|mesh-terms=* Adult
* Aged
* Apoptosis
* Brain Neoplasms
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Female
* Fibronectins
* Gene Expression Regulation, Neoplastic
* Glioma
* Humans
* Male
* Middle Aged
* Neoplasm Invasiveness
* Phosphatidylinositol 3-Kinases
* Proto-Oncogene Proteins c-akt
* Signal Transduction
|keywords=* Apoptosis
* Cell cycle
* Fibronectin 1
* Gene expression data
* Glioma
* PI3K/AKT signaling pathway
* Senescence
|full-text-url=https://sci-hub.do/10.1159/000492096
}}
{{medline-entry
|title=Cyclin D1 depletion interferes with oxidative balance and promotes cancer cell senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29880532
|abstract=Expression of cyclin D1 ([i]CCND1[/i]) is required for cancer cell survival and proliferation. This is presumably due to the role of cyclin D1 in inactivation of the RB tumor suppressor. Here, we investigated the pro-survival function of cyclin D1 in a number of cancer cell lines. We found that cyclin D1 depletion facilitated cellular senescence in several cancer cell lines. Senescence triggered by cyclin D1 depletion was more extensive than that caused by the prolonged [[CDK4]] inhibition. Intriguingly, the senescence caused by cyclin D1 depletion was independent of RB status of the cancer cell. We identified a build-up of intracellular reactive oxygen species in the cancer cells that underwent senescence upon depletion of cyclin D1 but not in those cells where [[CDK4]] was inhibited. The higher ROS levels were responsible for the cell senescence, which was instigated by the p38-JNK-FOXO3a-p27 pathway. Therefore, expression of cyclin D1 prevents cancer cells from undergoing senescence, at least partially, by keeping the level of intracellular oxidative stress at a tolerable sub-lethal level. Depletion of cyclin D1 promotes the RB-independent pro-senescence pathway and the cancer cells then succumb to the endogenous oxidative stress levels.This article has an associated First Person interview with the first author of the paper.
|mesh-terms=* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Cyclin D1
* Humans
* MCF-7 Cells
* Neoplasms
* Oxidative Stress
* Retinoblastoma Protein
|keywords=* CDK4
* Cyclin D1
* FOXO3a
* Oxidative stress
* Retinoblastoma protein
* Senescence
|full-text-url=https://sci-hub.do/10.1242/jcs.214726
}}
{{medline-entry
|title=Fucoidan Rescues p-Cresol-Induced Cellular Senescence in Mesenchymal Stem Cells via FAK-Akt-TWIST Axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29642406
|abstract=Mesenchymal stem cells ([[MSC]]s) are a source for cell-based therapy. Although [[MSC]]s have the potential for tissue regeneration, their therapeutic efficacy is restricted by the uremic toxin, [i]p[/i]-cresol, in chronic kidney disease (CKD). To address this issue, we investigated the effect of fucoidan, a marine sulfated polysaccharide, on cellular senescence in [[MSC]]s. After [i]p[/i]-cresol exposure, [[MSC]] senescence was induced, as indicated by an increase in cell size and a decrease in proliferation capacity. Treatment of senescent [[MSC]]s with fucoidan significantly reversed this cellular senescence via regulation of SMP30 and p21, and increased proliferation through the regulation of cell cycle-associated proteins (CDK2, [[CDK4]], cyclin D1, and cyclin E). These effects were dependent on FAK-Akt-TWIST signal transduction. In particular, fucoidan promoted the expression of cellular prion protein (PrP ), which resulted in the maintenance of cell expansion capacity in [i]p[/i]-cresol-induced senescent [[MSC]]s. This protective effect of fucoidan on senescence-mediated inhibition of proliferation was dependent on the TWIST-PrP  axis. In summary, this study shows that fucoidan protects against [i]p[/i]-cresol-induced cellular senescence in [[MSC]]s through activation of the FAK-Akt-TWIST pathway and suggests that fucoidan could be used in conjunction with functional [[MSC]]-based therapies in the treatment of CKD.
|mesh-terms=* Cell Cycle
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Cresols
* Focal Adhesion Kinase 1
* Humans
* Mesenchymal Stem Cell Transplantation
* Mesenchymal Stem Cells
* Nuclear Proteins
* Polysaccharides
* PrPC Proteins
* Proto-Oncogene Proteins c-akt
* Renal Insufficiency, Chronic
* Signal Transduction
* Twist-Related Protein 1
* Up-Regulation
|keywords=* cellular senescence
* chronic kidney disease
* fucoidan
* mesenchymal stem cells
* p-cresol
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923408
}}
{{medline-entry
|title=Carvacrol nanoemulsion evokes cell cycle arrest, apoptosis induction and autophagy inhibition in doxorubicin resistant-A549 cell line.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29405784
|abstract=Carvacrol is a monoterpenoid flavonoid found abundantly in thyme plants. Its physiochemical instability and partial solubility in water is the principal limitation for its industrial use. Hence, we made a carvacrol nanoemulsion (CANE) using ultrasonication method and characterized it by dynamic light scattering (DLS) technique which revealed a negative surface charge (-29.89 mV) with 99.1 nm average droplet size. CANE effectively induced apoptosis in doxorubicin-resistant A549 lung carcinoma cells (A549 ) evident by the elevated expression of apoptotic proteins such as Bax, Cytochrome C, and Cleaved caspase 3 and 9. Also, CANE displayed cell senescence leading to cell cycle arrest by reducing [[CDK2]], [[CDK4]], [[CDK6]], Cyclin E, Cyclin D1 and enhancing p21 protein expression. In addition, a potential role of CANE in the inhibition of autophagy was noted by evaluating the reduced conversion of LC-3 I to II. Beside this, a down-regulation of important autophagy markers [[ATG5]] and [[ATG7]] and upregulation of p62 were detected in response to CANE. We conclude that the synthesized CANE has potential to cause cell senescence, cell cycle arrest, autophagy inhibition and apoptosis in A549  cells and could be used as a potential candidate for lung cancer therapy.
|mesh-terms=* A549 Cells
* Animals
* Apoptosis
* Autophagy
* Cell Cycle Checkpoints
* Cellular Senescence
* Cymenes
* Dose-Response Relationship, Drug
* Doxorubicin
* Drug Resistance, Neoplasm
* Emulsions
* Humans
* Mice
* Mitochondria
* Monoterpenes
* Nanostructures
* Oxidative Stress
* Xenograft Model Antitumor Assays
|keywords=* Carvacrol nanoemulsion
* apoptosis
* autophagy
* cell senescence
|full-text-url=https://sci-hub.do/10.1080/21691401.2018.1434187
}}
{{medline-entry
|title=Mechanistic understanding of the role of [[ATRX]] in senescence provides new insight for combinatorial therapies with [[CDK4]] inhibitors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29404388
|abstract=Senescence is an irreversible form of growth arrest and is generally considered a favorable outcome of cancer therapies, yet little is known about the molecular events that distinguish this state from readily reversible growth arrest (i.e. quiescence). Recently, we discovered that during therapy induced senescence the chromatin remodeling protein α-thalassemia, mental retardation, X-linked ([[ATRX]]) represses Harvey rat sarcoma viral oncogene homolog ([i]HRAS)[/i], and repression of [i]HRAS[/i] is necessary to establish senescence, suggesting how new clinical combinations might be used to achieve durable senescence.

|keywords=* ATRX
* CDK4 inhibitors
* Therapy induced senescence
* geroconversion
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791849
}}
{{medline-entry
|title=Glutaredoxin-1 Silencing Induces Cell Senescence via p53/p21/p16 Signaling Axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29356545
|abstract=Glutaredoxin-1 (Grx1) catalyzes deglutathionylation with glutathione as a cofactor. Accumulating evidence indicates important roles for Grx1 and S-glutathionylation in the aging process; however, further exploration of Grx1-regulated cellular processes is important to understand the functions of Grx1 in aging. In the present study, we constructed stable Grx1 knockdown or overexpression human cell lines. Grx1 silencing significantly decreased the cellular ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) (GSH/GSSG ratio), resulting in excessive reactive oxygen species (ROS) accumulation, whereas Grx1 overexpression decreased cellular ROS levels. Grx1 silencing also increased glutathionylation of DJ-1 and HSP60, contributing to decreased mitochondrial spare respiration capacity and ATP production. We applied quantitative proteomics to identify differentially expressed proteins between Grx1 knockdown and control cells and showed that Grx1 silencing inactivated DNA replication and damage repair pathways. p53 signaling was activated by Grx1 silencing, which inhibited the [[CDK4]]-mediated G1-S transition, resulting in G1 phase cell-cycle arrest and cell senescence, a known hallmark of aging. Taken together, our results indicate that Grx1 regulates DNA replication and damage repair processes and is a potential therapeutic target for aging-related diseases.
|mesh-terms=* Cell Line, Tumor
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* DNA Damage
* DNA Repair
* Gene Expression Regulation
* Glutaredoxins
* Glutathione
* HEK293 Cells
* Hep G2 Cells
* Humans
* Hydrogen Peroxide
* Metabolome
* Neuroglia
* Oxidation-Reduction
* Oxidative Stress
* Oxygen Consumption
* Proteome
* RNA, Small Interfering
* Reactive Oxygen Species
* Signal Transduction
* Tumor Suppressor Protein p53
|keywords=* Glutaredoxin-1
* S-glutathionylation
* cell senescence
* proteomics
* redox signaling
|full-text-url=https://sci-hub.do/10.1021/acs.jproteome.7b00761
}}
{{medline-entry
|title=Inhibition of [[CIP2A]] attenuates tumor progression by inducing cell cycle arrest and promoting cellular senescence in hepatocellular carcinoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29175329
|abstract=[[CIP2A]] is a recent identified oncogene that inhibits protein phosphatase 2A (PP2A) and stabilizes c-Myc in cancer cells. To investigate the potential oncogenic role and prognostic value of [[CIP2A]], we comprehensively analyzed the [[CIP2A]] expression levels in pan-cancer and observed high expression level of [[CIP2A]] in majority cancer types, including hepatocellular carcinoma (HCC). Based on a validation cohort including 60 HCC and 20 non-tumorous tissue samples, we further confirmed the high mRNA and protein expression levels of [[CIP2A]] in HCC, and found high [[CIP2A]] mRNA expression level was associated with unfavorable overall and recurrence-free survival in patients with HCC. Mechanistic investigations revealed that inhibition of [[CIP2A]] significantly attenuated cellular proliferation in vitro and tumourigenicity in vivo. Bioinformatic analysis suggested that [[CIP2A]] might be involved in regulating cell cycle. Our experimental data further confirmed [[CIP2A]] knockdown induced cell cycle arrest at G1 phase. We found accumulated cellular senescence in HCC cells with [[CIP2A]] knockdown, companying expression changes of senescence associated proteins (p21, [[CDK2]], [[CDK4]], cyclin D1, [[MCM7]] and FoxM1). Mechanistically, [[CIP2A]] knockdown repressed FoxM1 expression and induced FoxM1 dephosphorylation. Moreover, inhibition of PP2A by phosphatase inhibitor rescued the repression of FoxM1. Taken together, our results showed that [[CIP2A]] was highly expressed in HCC. Inhibition of [[CIP2A]] induced cell cycle arrest and promoted cellular senescence via repressing FoxM1 transcriptional activity, suggesting a potential anti-cancer target for patients with HCC.
|mesh-terms=* Autoantigens
* Biomarkers, Tumor
* Carcinoma, Hepatocellular
* Cell Cycle Checkpoints
* Cell Line, Tumor
* Cellular Senescence
* Disease Progression
* Forkhead Box Protein M1
* Gene Expression
* Gene Knockdown Techniques
* Hep G2 Cells
* Humans
* Intracellular Signaling Peptides and Proteins
* Liver Neoplasms
* Membrane Proteins
* Oncogenes
* Prognosis
* RNA, Messenger
* RNA, Neoplasm
|keywords=* CIP2A
* Cell cycle
* Cellular senescence
* FoxM1
* Hepatocellular carcinoma
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2017.11.124
}}
{{medline-entry
|title=Preclinical characterization of abemaciclib in hormone receptor positive breast cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29050219
|abstract=Abemaciclib is an ATP-competitive, reversible kinase inhibitor selective for [[CDK4]] and [[CDK6]] that has shown antitumor activity as a single agent in hormone receptor positive (HR ) metastatic breast cancer in clinical trials. Here, we examined the mechanistic effects of abemaciclib treatment using [i]in vitro[/i] and [i]in vivo[/i] breast cancer models. Treatment of estrogen receptor positive (ER ) breast cancer cells with abemaciclib alone led to a decrease in phosphorylation of Rb, arrest at G1, and a decrease in cell proliferation. Moreover, abemaciclib exposure led to durable inhibition of pRb, TopoIIα expression and DNA synthesis, which were maintained after drug removal. Treatment of ER  breast cancer cells also led to a senescence response as indicated by accumulation of β-galactosidase, formation of senescence-associated heterochromatin foci, and a decrease in [[FOXM1]] positive cells. Continuous exposure to abemaciclib altered breast cancer cell metabolism and induced apoptosis. In a xenograft model of ER  breast cancer, abemaciclib monotherapy caused regression of tumor growth. Overall these data indicate that abemaciclib is a [[CDK4]] and [[CDK6]] inhibitor that, as a single agent, blocks breast cancer cell progression, and upon longer treatment can lead to sustained antitumor effects through the induction of senescence, apoptosis, and alteration of cellular metabolism.

|keywords=* abemaciclib
* apoptosis
* cell cycle
* hormone receptor positive breast cancer
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642494
}}
{{medline-entry
|title=Immortalized prairie vole-derived fibroblasts (VMF-K4DTs) can be transformed into pluripotent stem cells and provide a useful tool with which to determine optimal reprogramming conditions.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28331164
|abstract=The cellular conditions required to establish induced pluripotent stem cells (iPSCs), such as the number of reprogramming factors and/or promoter selection, differ among species. The establishment of iPSCs derived from cells of previously unstudied species therefore requires the extensive optimization of programming conditions, including promoter selection and the optimal number of reprogramming factors, through a trial-and-error approach. While the four Yamanaka factors Oct3/4, Sox2, Klf4, and c-Myc are sufficient for iPSC establishment in mice, we reported previously that six reprogramming factors were necessary for the creation of iPSCs from primary prairie vole-derived cells. Further to this study, we now show detailed data describing the optimization protocol we developed in order to obtain iPSCs from immortalized prairie vole-derived fibroblasts. Immortalized cells can be very useful tools in the optimization of cellular reprogramming conditions, as cellular senescence is known to dramatically decrease the efficiency of iPSC establishment. The immortalized prairie vole cells used in this optimization were designated K4DT cells as they contained mutant forms of [[CDK4]], cyclin D, and telomerase reverse transcriptase ([[TERT]]). We show that iPSCs derived from these immortalized cells exhibit the transcriptional silencing of exogenous reprogramming factors while maintaining pluripotent cell morphology. There were no observed differences between the iPSCs derived from primary and immortalized prairie vole fibroblasts. Our data suggest that cells that are immortalized with mutant [[CDK4]], cyclin D, and [[TERT]] provide a useful tool for the determination of the optimal conditions for iPSC establishment.
|mesh-terms=* Animals
* Arvicolinae
* Cellular Reprogramming
* Fibroblasts
* Genetic Vectors
* HEK293 Cells
* Humans
* Induced Pluripotent Stem Cells
* Lentivirus
* Primary Cell Culture
|keywords=* Cellular senescence
* Immortalized cells
* Induced pluripotent stem cell (iPSC)
* Pluripotency
* Prairie vole
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481634
}}
{{medline-entry
|title=Molecular mechanism of G  arrest and cellular senescence induced by LEE011, a novel [[CDK4]]/CDK6 inhibitor, in leukemia cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28286417
|abstract=Overexpression of cyclin D1 dependent kinases 4 and 6 ([[CDK4]]/6) is a common feature of many human cancers including leukemia. LEE011 is a novel inhibitor of both [[CDK4]] and 6. To date, the molecular function of LEE011 in leukemia remains unclear. Leukemia cell growth and apoptosis following LEE011 treatment was assessed through [[CCK]]-8 and annexin V/propidium iodide staining assays. Cell senescence was assessed by β-galactosidase staining and p16  expression analysis. Gene expression profiles of LEE011 treated HL-60 cells were investigated using an Arraystar Human LncRNA array. Gene ontology and KEGG pathway analysis were then used to analyze the differentially expressed genes from the cluster analysis. Our studies demonstrated that LEE011 inhibited proliferation of leukemia cells and could induce apoptosis. Hoechst 33,342 staining analysis showed DNA fragmentation and distortion of nuclear structures following LEE011 treatment. Cell cycle analysis showed LEE011 significantly induced cell cycle G  arrest in seven of eight acute leukemia cells lines, the exception being THP-1 cells. β-Galactosidase staining analysis and p16  expression analysis showed that LEE011 treatment can induce cell senescence of leukemia cells. LncRNA microarray analysis showed 2083 differentially expressed mRNAs and 3224 differentially expressed lncRNAs in LEE011-treated HL-60 cells compared with controls. Molecular function analysis showed that LEE011 induced senescence in leukemia cells partially through downregulation of the transcriptional expression of [[MYBL2]]. We demonstrate for the first time that LEE011 treatment results in inhibition of cell proliferation and induction of G  arrest and cellular senescence in leukemia cells. LncRNA microarray analysis showed differentially expressed mRNAs and lncRNAs in LEE011-treated HL-60 cells and we demonstrated that LEE011 induces cellular senescence partially through downregulation of the expression of [[MYBL2]]. These results may open new lines of investigation regarding the molecular mechanism of LEE011 induced cellular senescence.

|keywords=* Arraystar Human LncRNA array
* CDK4/6
* Cellular senescence
* LEE011
* Leukemia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340031
}}
{{medline-entry
|title=p16 loss rescues functional decline of Brca1-deficient mammary stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28278054
|abstract=Recent evidence indicates that the accumulation of endogenous DNA damage can induce senescence and limit the function of adult stem cells. It remains elusive whether deficiency in DNA damage repair is associated with the functional alteration of mammary stem cells. In this article, we reported that senescence was induced in mammary epithelial cells during aging along with increased expression of p16Ink4a (p16), an inhibitor of [[CDK4]] and CKD6. Loss of p16 abrogated the age-induced senescence in mammary epithelial cells and significantly increased mammary stem cell function. We showed that loss of Brca1, a tumor suppressor that functions in DNA damage repair, in the mammary epithelium induced senescence with induction of p16 and a decline of stem cell function, which was rescued by p16 loss. These data not only answer the question as to whether deficiency in DNA damage repair is associated with the functional decline of mammary stem cells, but also identify the role of p16 in suppressing Brca1-deficient mammary stem cell function.
|mesh-terms=* Aging
* Animals
* BRCA1 Protein
* Cyclin-Dependent Kinase Inhibitor p16
* Epithelial Cells
* Epithelium
* Female
* Mammary Glands, Animal
* Mice
* Stem Cells
* Tumor Suppressor Proteins
|keywords=* Brca1
* p16INK4a
* senescence
* stem cell function
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405722
}}
{{medline-entry
|title=p16  enhances the transcriptional and the apoptotic functions of p53 through DNA-dependent interaction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28218424
|abstract=p16  and p53 are two important tumor suppressor proteins that play essential roles during cell proliferation and aging through regulating the expression of several genes. Here, we report that p16  and p53 co-regulate a plethora of transcripts. Furthermore, both proteins colocalize in the nucleus of human primary skin fibroblasts and breast luminal cells, and form a heteromer whose level increases in response to genotoxic stress as well as aging of human fibroblasts and various mouse organs. [[CDK4]] is also present in this heteromeric complex, which is formed only in the presence of DNA both in vitro using pure recombinant proteins and in vivo. We have also shown that p16  enhances the binding efficiency of p53 to its cognate sequence presents in the [[CDKN1A]] promoter in vitro, and both proteins are present at the promoters of [[CDKN1A]] and [[BAX]] in vivo. Importantly, the fourth ankyrin repeat of p16  and the C-terminal domain of p53 were necessary for the physical association between these two proteins. The physiologic importance of this association was revealed by the inability of cancer-associated p16  mutants to interact with p53 and to transactivate the expression of its major targets [[CDKN1A]] and [[BAX]] in the p16-defective U2OS cells expressing either wild-type or mutated p16  . Furthermore, the association between p16  and p53 was capital for their nuclear colocalization, the X-ray-dependent induction of p21 and Bax proteins as well as the induction of apoptosis in various types of cells. Together, these results show DNA-dependent physical interaction between p16  and p53.
|mesh-terms=* Animals
* Apoptosis
* Cell Proliferation
* Cells, Cultured
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* DNA
* Embryo, Mammalian
* Female
* Fibroblasts
* Gene Expression Regulation
* Humans
* Mice
* Mice, Inbred C57BL
* Promoter Regions, Genetic
* Transcription, Genetic
* Tumor Suppressor Protein p53
* bcl-2-Associated X Protein
|keywords=* aging
* apoptosis
* heterocomplex
* p16INK4A
* p53
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266037
}}
{{medline-entry
|title=p16INK4a suppresses [[BRCA1]]-deficient mammary tumorigenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27811360
|abstract=Senescence prevents the proliferation of genomically damaged, but otherwise replication competent cells at risk of neoplastic transformation. p16INK4A (p16), an inhibitor of [[CDK4]] and [[CDK6]], plays a critical role in controlling cellular senescence in multiple organs. Functional inactivation of p16 by gene mutation and promoter methylation is frequently detected in human breast cancers. However, deleting p16 in mice or targeting DNA methylation within the murine p16 promoter does not result in mammary tumorigenesis. How loss of p16 contributes to mammary tumorigenesis in vivo is not fully understood.In this article, we reported that disruption of Brca1 in the mammary epithelium resulted in premature senescence that was rescued by p16 loss. We found that p16 loss transformed Brca1-deficient mammary epithelial cells and induced mammary tumors, though p16 loss alone was not sufficient to induce mammary tumorigenesis. We demonstrated that loss of both p16 and Brca1 led to metastatic, basal-like, mammary tumors with the induction of EMT and an enrichment of tumor initiating cells. We discovered that promoter methylation silenced p16 expression in most of the tumors developed in mice heterozygous for p16 and lacking Brca1. These data not only identified the function of p16 in suppressing [[BRCA1]]-deficient mammary tumorigenesis, but also revealed a collaborative effect of genetic mutation of p16 and epigenetic silencing of its transcription in promoting tumorigenesis. To the best of our knowledge, this is the first genetic evidence directly showing that p16 which is frequently deleted and inactivated in human breast cancers, collaborates with Brca1 controlling mammary tumorigenesis.
|mesh-terms=* Animals
* BRCA1 Protein
* Cell Transformation, Neoplastic
* Cells, Cultured
* Cyclin-Dependent Kinase Inhibitor p16
* DNA Methylation
* Epithelial Cells
* Female
* Gene Expression Regulation, Neoplastic
* Humans
* Mammary Neoplasms, Animal
* Mice, Knockout
* Mice, Transgenic
* Promoter Regions, Genetic
|keywords=* brca1
* breast cancer
* p16INK4a
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356676
}}
{{medline-entry
|title=A steroid like phytochemical Antcin M is an anti-aging reagent that eliminates hyperglycemia-accelerated premature senescence in dermal fibroblasts by direct activation of Nrf2 and SIRT-1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27542238
|abstract=The present study revealed the anti-aging properties of antcin M (ANM) and elucidated the molecular mechanism underlying the effects. We found that exposure of human normal dermal fibroblasts (HNDFs) to high-glucose (HG, 30 mM) for 3 days, accelerated G0/G1 phase arrest and senescence. Indeed, co-treatment with ANM (10 µM) significantly attenuated HG-induced growth arrest and promoted cell proliferation. Further molecular analysis revealed that ANM blocked the HG-induced reduction in G1-S transition regulatory proteins such as cyclin D, cyclin E, [[CDK4]], [[CDK6]], [[CDK2]] and protein retinoblastoma (pRb). In addition, treatment with ANM eliminated HG-induced reactive oxygen species (ROS) through the induction of anti-oxidant genes, HO-1 and NQO-1 via transcriptional activation of Nrf2. Moreover, treatment with ANM abolished HG-induced SIPS as evidenced by reduced senescence-associated β-galactosidase (SA-β-gal) activity. This effect was further confirmed by reduction in senescence-associated marker proteins including, p21CIP1, p16INK4A, and p53/FoxO1 acetylation. Also, the HG-induced decline in aging-related marker protein SMP30 was rescued by ANM. Furthermore, treatment with ANM increased SIRT-1 expression, and prevented SIRT-1 depletion. This protection was consistent with inhibition of SIRT-1 phosphorylation at Ser47 followed by blocking its upstream kinases, p38 MAPK and JNK/SAPK. Further analysis revealed that ANM partially protected HG-induced senescence in SIRT-1 silenced cells. A similar effect was also observed in Nrf2 silenced cells. However, a complete loss of protection was observed in both Nrf2 and SIRT-1 knockdown cells suggesting that both induction of Nrf2-mediated anti-oxidant defense and SIRT-1-mediated deacetylation activity contribute to the anti-aging properties of ANM in vitro. Result of in vivo studies shows that ANM-treated C. elegens exhibits an increased survival rate during HG-induced oxidative stress insult. Furthermore, ANM significantly extended the life span of C. elegans. Taken together, our results suggest the potential application of ANM in age-related diseases or as a preventive reagent against aging process.
|mesh-terms=* Acetylcysteine
* Antioxidants
* Antrodia
* Apoptosis
* Cell Cycle
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Cholestenones
* Endothelial Cells
* Fibroblasts
* Gene Silencing
* Glucose
* Humans
* Hyperglycemia
* Medicine, Chinese Traditional
* NF-E2-Related Factor 2
* Oxidative Stress
* Phosphorylation
* Phytochemicals
* Reactive Oxygen Species
* Resveratrol
* Retinoblastoma Protein
* Sirtuin 1
* Skin
* Stilbenes
* Triterpenes
|keywords=* Antcin M
* Gerotarget
* SIRT-1
* antrodia salmonea
* hyperglycemia
* stress-induced premature senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325331
}}
{{medline-entry
|title=[[CDK4]]-[[CDK6]] inhibitors induce autophagy-mediated degradation of [[DNMT1]] and facilitate the senescence antitumor response.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27532423
|abstract=Senescence is a natural anticancer defense program disabled in tumor cells. We discovered that deregulated [[CDK4]] (cyclin dependant kinase 4) and [[CDK6]] activities contribute to senescence bypass during tumorigenesis and that their inhibition restores the senescence response in tumor cells. [[CDK4]] and [[CDK6]] phosphorylate RB1/RB, preventing its inhibitory interaction with the E2Fs, the cell cycle transcription factors. However, we also found that [[CDK4]] interacts and phosphorylates the [[DNMT1]] (DNA methyltransferase 1) protein protecting it from macroautophagy/autophagy-mediated protein degradation. This discovery highlights a new epigenetic component of [[CDK4]]-[[CDK6]] signaling that could be exploited in cancer treatment.
|mesh-terms=* Autophagy
* Cellular Senescence
* Clinical Trials as Topic
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase 6
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* Humans
* Models, Biological
* Neoplasms
* Protein Kinase Inhibitors
* Proteolysis
|keywords=* CDK4
* DNMT1
* PML
* autophagy
* cancer
* epigenetic
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079664
}}
{{medline-entry
|title=Sperm-associated antigen 9 ([[SPAG9]]) promotes the survival and tumor growth of triple-negative breast cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27449044
|abstract=Recently, we demonstrated the association of sperm-associated antigen 9 ([[SPAG9]]) expression with breast cancer. Among breast cancer, 15 % of the cancers are diagnosed as triple-negative breast cancers (TNBC) based on hormone receptor status and represent an important clinical challenge because of lack of effective available targeted therapy. Therefore, in the present investigation, plasmid-based small hairpin (small hairpin RNA (shRNA)) approach was used to ablate [[SPAG9]] in aggressive breast cancer cell line model (MDA-[[MB]]-231) in order to understand the role of [[SPAG9]] at molecular level in apoptosis, cell cycle, and epithelial-to-mesenchymal transition (EMT) signaling. Our data in MDA-[[MB]]-231 cells showed that ablation of [[SPAG9]] resulted in membrane blebbing, increased mitochondrial membrane potential, DNA fragmentation, phosphatidyl serine surface expression, and caspase activation. [[SPAG9]] depletion also resulted in cell cycle arrest in G0-G1 phase and induced cellular senescence. In addition, in in vitro and in vivo xenograft studies, ablation of [[SPAG9]] resulted in upregulation of p21 along with pro-apoptotic molecules such as BAK, [[BAX]], BIM, [[BID]], NOXA, AIF, Cyto-C, [[PARP1]], [[APAF1]], Caspase 3, and Caspase 9 and epithelial marker, E-cadherin. Also, [[SPAG9]]-depleted cells showed downregulation of cyclin B1, cyclin D1, cyclin E, [[CDK1]], [[CDK4]], [[CDK6]], [[BCL2]], Bcl-xL, [[XIAP]], cIAP2, [[MCL1]], GRP78, SLUG, SNAIL, TWIST, vimentin, N-cadherin, [[MMP2]], [[MMP3]], [[MMP9]], SMA, and β-catenin. Collectively, our data suggests that [[SPAG9]] promotes tumor growth by inhibiting apoptosis, altering cell cycle, and enhancing EMT signaling in in vitro cells and in vivo mouse model. Hence, [[SPAG9]] may be a potential novel target for therapeutic use in TNBC treatment.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Animals
* Apoptosis
* Blotting, Western
* Cell Proliferation
* Fluorescent Antibody Technique, Indirect
* Humans
* Immunoenzyme Techniques
* Membrane Potential, Mitochondrial
* Mice
* RNA, Small Interfering
* Triple Negative Breast Neoplasms
* Tumor Cells, Cultured
|keywords=* Apoptosis
* Cell growth
* Cellular motility
* SPAG9
* Senescence
* Triple-negative breast cancer
* Tumor growth
|full-text-url=https://sci-hub.do/10.1007/s13277-016-5240-6
}}
{{medline-entry
|title=Double staining of β-galactosidase with fibrosis and cancer markers reveals the chronological appearance of senescence in liver carcinogenesis induced by diethylnitrosamine.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26589970
|abstract=Cellular senescence is characterized by irreversible cell arrest and is associated with the development of chronic diseases, including cancer. Here, we investigated the induction of cellular senescence during liver carcinogenesis. Liver cancer was induced in Fischer 344 rats with a weekly intraperitoneal injection of diethylnitrosamine (50mg/kg body weight) for 16 weeks. Double-detection of β-galactosidase with Ki67 for cell proliferation; a-SMA and Pdgfrb for cell specificity; p53, p21, p16, and cyclin D1, [[CDK2]], and [[CDK4]] for senescence-associated molecular pathways and γ-glutamyltranspeptidase (GGT) for hepatocarcinogenesis was assessed to determine the association of these markers with cellular senescence. DNA damage was measured through senescence-associated heterochromatin foci (SAHF) detection. Progressive cellular senescence was observed in both fibrotic septa and hepatocytes from week 10 to 18. The maximum peak of positive senescent and fibrotic cells was observed at week 16 and decreased at week 18, but cell proliferation remained high. Whereas the increased p16 expression and SAHF were concomitant with that of β-galactosidase, those of p53 and p21 were barely detected. Furthermore, β-galactosidase positive myofibroblast-like cells were mainly surrounding GGT-positive tumors. Our findings showed that in hepatocarcinogenesis by diethylnitrosamine, cellular senescence is associated with p16 pathway activation and is mainly localized in myofibroblast-like cells. 
|mesh-terms=* Animals
* Biomarkers, Tumor
* Carcinogenesis
* Carcinogens
* Cell Proliferation
* Cellular Senescence
* DNA Damage
* Diethylnitrosamine
* Fibrosis
* Ki-67 Antigen
* Liver Neoplasms
* Male
* Neoplasms
* Rats
* Rats, Inbred F344
* beta-Galactosidase
* gamma-Glutamyltransferase
|keywords=* Fibrosis
* Hepatocarcinogenesis
* N-Diethylnitrosamine
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.toxlet.2015.11.011
}}
{{medline-entry
|title=Efficacy of [[CDK4]] inhibition against sarcomas depends on their levels of [[CDK4]] and p16ink4 mRNA.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26528855
|abstract=Sarcomas are malignant tumors accounting for a high percentage of cancer morbidity and mortality in children and young adults. Surgery and radiation therapy are the accepted treatments for most sarcomas; however, patients with metastatic disease are treated with systemic chemotherapy. Many tumors display marginal levels of chemoresponsiveness and new treatment approaches are needed. Deregulation of the G1 checkpoint is crucial for various oncogenic transformation processes, suggesting that many cancer cell types depend on [[CDK4]]/6 activity. Thus, [[CDK4]]/6 activity appears to represent a promising therapeutic target for cancer treatment. In the present work, we explore the efficacy of [[CDK4]] inhibition using palbociclib (PD0332991), a highly selective inhibitor of [[CDK4]]/6, in a panel of sarcoma cell lines and sarcoma tumor xenografts (PDXs). Palbociclib induces senescence in these cell lines and the responsiveness of these cell lines correlated with their levels of [[CDK4]] mRNA. Palbociclib is also active in vivo against sarcomas displaying high levels of [[CDK4]] but not against sarcomas displaying low levels of [[CDK4]] and high levels of p16ink4a. The analysis of tumors growing after palbociclib showed a clear decrease in the [[CDK4]] levels, indicating that clonal selection occurred in these treated tumors. In summary, our data support the efficacy of [[CDK4]] inhibitors against sarcomas displaying increased [[CDK4]] levels, particularly fibrosarcomas and MPNST. Our results also suggest that high levels of p16ink4a may indicate poor efficacy of [[CDK4]] inhibitors. 
|mesh-terms=* Adult
* Animals
* Apoptosis
* Blotting, Western
* Cell Proliferation
* Cellular Senescence
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase Inhibitor p16
* Humans
* Immunoenzyme Techniques
* Mice
* Mice, Nude
* Microarray Analysis
* Protein Kinase Inhibitors
* RNA, Messenger
* Real-Time Polymerase Chain Reaction
* Reverse Transcriptase Polymerase Chain Reaction
* Sarcoma
* Tumor Cells, Cultured
* Xenograft Model Antitumor Assays
|keywords=* CDKs
* cell cycle
* cellular senescence
* cyclin dependent kinase inhibitor
* sarcomas
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747352
}}
{{medline-entry
|title=Suppression of [[RAD21]] Induces Senescence of MDA-[[MB]]-231 Human Breast Cancer Cells Through [[RB1]] Pathway Activation Via c-Myc Downregulation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26529363
|abstract=Cellular senescence impedes cancer progression by limiting uncontrolled cell proliferation. To identify new genetic events controlling senescence, we performed a small interfering RNA screening human cancer cells and identified a number of targets potentially involved in senescence of MDA-[[MB]]-231 human breast cancer cells. Importantly, we showed that knockdown of [[RAD21]] resulted in the appearance of several senescent markers, including enhanced senescence-associated β-galactosidase activity and heterochromatin focus formation, as well as elevated p21 protein levels and [[RB1]] pathway activation. Further biochemical analyses revealed that [[RAD21]] knockdown led to the downregulation of c-Myc and its targets, including [[CDK4]], a negative regulator of [[RB1]], and blocked[[RB1]] phosphorylation (p[[RB1]]), and the [[RB1]]-mediated transcriptional repression of E2F. Moreover, c-Myc downregulation was partially mediated by proteasome-dependent degradation within promyelocytic leukemia (PML) nuclear bodies, which were found to be highly abundant during [[RAD21]] knockdown-induced senescence. Exogenous c-Myc reconstitution rescued cells from [[RAD21]] silencing-induced senescence. Altogether, data arising from this study implicate a novel function of [[RAD21]] in cellular senescence in MDA-[[MB]]-231 cells that is mainly dependent on[[RB1]] pathway activation via c-Myc downregulation.
|mesh-terms=* Breast Neoplasms
* Cell Cycle Proteins
* Cell Line, Tumor
* Cellular Senescence
* DNA-Binding Proteins
* Down-Regulation
* Female
* Gene Expression Regulation, Neoplastic
* Gene Knockdown Techniques
* Humans
* Nuclear Proteins
* Phosphoproteins
* Proto-Oncogene Proteins c-myc
* RNA, Small Interfering
* Retinoblastoma Binding Proteins
* Signal Transduction
* Ubiquitin-Protein Ligases
|keywords=* MDA-MB-231
* RAD21
* RB1
* SENESCENCE
* c-Myc
|full-text-url=https://sci-hub.do/10.1002/jcb.25426
}}
{{medline-entry
|title=Molecular differences between stromal cell populations from deciduous and permanent human teeth.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25927523
|abstract=Deciduous and permanent human teeth represent an excellent model system to study aging of stromal populations. Aging is tightly connected to self-renewal and proliferation and thus, mapping potential molecular differences in these characteristics between populations constitutes an important task. Using specifically designed microarray panels, Real-Time Quantitative Polymerase Chain Reaction (RT q-PCR), Western blot, immunohistochemistry and siRNA-mediated knock down experiments, we have detected a number of molecules that were differentially expressed in dental pulp from deciduous and permanent teeth extracted from young children and adults, respectively. Among the differentially regulated genes, high-mobility group AT-hook 2 ([[HMGA2]]), a stem cell-associated marker, stood out as a remarkable example with a robust expression in deciduous pulp cells. siRNA-mediated knock down of [[HMGA2]] expression in cultured deciduous pulp cells caused a down-regulated expression of the pluripotency marker [[NANOG]]. This finding indicates that [[HMGA2]] is a pulpal stem cell regulatory factor. In addition to this, we discovered that several proliferation-related genes, including CDC2A and [[CDK4]], were up-regulated in deciduous pulp cells, while matrix genes [[COL1A1]], fibronectin and several signaling molecules, such as VEGF, FGFr-1 and IGFr-1 were up-regulated in the pulp cells from permanent teeth. Taken together, our data suggest that deciduous pulp cells are more robust in self- renewal and proliferation, whereas adult dental pulp cells are more capable of signaling and matrix synthesis.
|mesh-terms=* Adult
* Aging
* CDC2 Protein Kinase
* Cell Proliferation
* Cells, Cultured
* Child
* Child, Preschool
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinases
* Dental Pulp
* Down-Regulation
* HMGA2 Protein
* Homeodomain Proteins
* Humans
* Middle Aged
* Nanog Homeobox Protein
* Oligonucleotide Array Sequence Analysis
* RNA Interference
* RNA, Small Interfering
* Stromal Cells
* Tooth, Deciduous
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417277
}}
{{medline-entry
|title=Functional Effect of Pim1 Depends upon Intracellular Localization in Human Cardiac Progenitor Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25882843
|abstract=Human cardiac progenitor cells (hCPC) improve heart function after autologous transfer in heart failure patients. Regenerative potential of hCPCs is severely limited with age, requiring genetic modification to enhance therapeutic potential. A legacy of work from our laboratory with Pim1 kinase reveals effects on proliferation, survival, metabolism, and rejuvenation of hCPCs in vitro and in vivo. We demonstrate that subcellular targeting of Pim1 bolsters the distinct cardioprotective effects of this kinase in hCPCs to increase proliferation and survival, and antagonize cellular senescence. Adult hCPCs isolated from patients undergoing left ventricular assist device implantation were engineered to overexpress Pim1 throughout the cell (PimWT) or targeted to either mitochondrial (Mito-Pim1) or nuclear (Nuc-Pim1) compartments. Nuc-Pim1 enhances stem cell youthfulness associated with decreased senescence-associated β-galactosidase activity, preserved telomere length, reduced expression of p16 and p53, and up-regulation of nucleostemin relative to PimWT hCPCs. Alternately, Mito-Pim1 enhances survival by increasing expression of Bcl-2 and Bcl-XL and decreasing cell death after H2O2 treatment, thereby preserving mitochondrial integrity superior to PimWT. Mito-Pim1 increases the proliferation rate by up-regulation of cell cycle modulators Cyclin D, [[CDK4]], and phospho-Rb. Optimal stem cell traits such as proliferation, survival, and increased youthful properties of aged hCPCs are enhanced after targeted Pim1 localization to mitochondrial or nuclear compartments. Targeted Pim1 overexpression in hCPCs allows for selection of the desired phenotypic properties to overcome patient variability and improve specific stem cell characteristics. 
|mesh-terms=* Apoptosis
* Cell Cycle
* Cell Nucleus
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Gene Expression Regulation
* Green Fluorescent Proteins
* Heart
* Heart Failure
* Heart Ventricles
* Humans
* Lentivirus
* Mitochondria
* Myocardium
* Phenotype
* Proto-Oncogene Proteins c-pim-1
* Regeneration
* Stem Cells
* Subcellular Fractions
* beta-Galactosidase
|keywords=* Pim1
* aging
* apoptosis
* heart failure
* human cardiac progenitor cell
* proliferation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447967
}}
{{medline-entry
|title=[[MDM2]] turnover and expression of [[ATRX]] determine the choice between quiescence and senescence in response to [[CDK4]] inhibition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25803170
|abstract=[[CDK4]] inhibitors ([[CDK4]]i) earned Breakthrough Therapy Designation from the FDA last year and are entering phase III clinical trials in several cancers. However, not all tumors respond favorably to these drugs. [[CDK4]] activity is critical for progression through G1 phase and into the mitotic cell cycle. Inhibiting this kinase induces Rb-positive cells to exit the cell cycle into either a quiescent or senescent state. In this report, using well-differentiated and dedifferentiated liposarcoma (WD/DDLS) cell lines, we show that the proteolytic turnover of [[MDM2]] is required for [[CDK4]]i-induced senescence. Failure to reduce [[MDM2]] does not prevent [[CDK4]]i-induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state. Reducing [[MDM2]] in these cells drives them into the more stable senescent state. [[CDK4]]i-induced senescence associated with loss of [[MDM2]] is also observed in some breast cancer, lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which [[MDM2]] is overexpressed or in cells that contain wild type p53. [[MDM2]] turnover depends on its E3 ligase activity and expression of [[ATRX]]. Interestingly, in seven patients the changes in [[MDM2]] expression were correlated with outcome. These insights identify [[MDM2]] and [[ATRX]] as new regulators controlling geroconversion, the process by which quiescent cells become senescent, and this insight may be exploited to improve the activity of [[CDK4]]i in cancer therapy.
|mesh-terms=* Breast Neoplasms
* Cell Line, Tumor
* Cellular Senescence
* Cyclin-Dependent Kinase 4
* DNA Helicases
* Gene Knockdown Techniques
* Humans
* Liposarcoma
* Nuclear Proteins
* Phosphorylation
* Piperazines
* Proto-Oncogene Proteins c-mdm2
* Pyridines
* Retinoblastoma Protein
* X-linked Nuclear Protein
|keywords=* ATRX
* CDK4 inhibitors
* MDM2
* geroconversion
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480747
}}
{{medline-entry
|title=Evidence for a [[CDK4]]-dependent checkpoint in a conditional model of cellular senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25695870
|abstract=Cellular senescence, the stable cell cycle arrest elicited by various forms of stress, is an important facet of tumor suppression. Although much is known about the key players in the implementation of senescence, including the pRb and p53 axes and the cyclin dependent kinase inhibitors p16(INK4a) and p21(CIP1), many details remain unresolved. In studying conditional senescence in human fibroblasts that express a temperature sensitive SV40 large T-antigen (T-Ag), we uncovered an unexpected role for [[CDK4]]. At the permissive temperature, where pRb and p53 are functionally compromised by T-Ag, cyclin D-[[CDK4]] complexes are disrupted by the high p16(INK4a) levels and reduced expression of p21(CIP1). In cells arrested at the non-permissive temperature, p21(CIP1) promotes reassembly of cyclin D-[[CDK4]] yet pRb is in a hypo-phosphorylated state, consistent with cell cycle arrest. In exploring whether the reassembled cyclin D-[[CDK4]]-p21 complexes are functional, we found that shRNA-mediated knockdown or chemical inhibition of [[CDK4]] prevented the increase in cell size associated with the senescent phenotype by allowing the cells to arrest in G1 rather than G2/M. The data point to a role for [[CDK4]] kinase activity in a G2 checkpoint that contributes to senescence. 
|mesh-terms=* Antigens, Polyomavirus Transforming
* Cell Cycle Checkpoints
* Cell Line
* Cellular Senescence
* Cyclin D1
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase 6
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* Humans
* Models, Biological
* Phenotype
* Piperazines
* Pyridines
* RNA Interference
* RNA, Small Interfering
* Retinoblastoma Protein
* Temperature
* Tumor Suppressor Protein p53
|keywords=* BrdU, bromodeoxyuridine
* CDK, cyclin dependent kinase
* CDK4
* FACS, fluorescence actvated cell sorting
* HFs, human fibroblasts
* PI, propidium iodide
* SA-βgal, senescence-associated β-galactosidase activity
* SV40 T-antigen
* SV40, simian virus 40
* TERT, telomerase reverse transcriptase
* human fibroblasts
* p16INK4a
* p21CIP1
* p53
* pRb, retinoblastoma protein
* retinoblastoma protein
* senescence
* shRNA, short-hairpin RNA
* ts, temperature sensitive
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613988
}}
{{medline-entry
|title=MiR-506 suppresses proliferation and induces senescence by directly targeting the [[CDK4]]/6-[[FOXM1]] axis in ovarian cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24604117
|abstract=Ovarian carcinoma is the most lethal gynaecological malignancy. Better understanding of the molecular pathogenesis of this disease and effective targeted therapies are needed to improve patient outcomes. MicroRNAs play important roles in cancer progression and have the potential for use as either therapeutic agents or targets. Studies in other cancers have suggested that miR-506 has anti-tumour activity, but its function has yet to be elucidated. We found that deregulation of miR-506 in ovarian carcinoma promotes an aggressive phenotype. Ectopic over-expression of miR-506 in ovarian cancer cells was sufficient to inhibit proliferation and to promote senescence. We also demonstrated that [[CDK4]] and [[CDK6]] are direct targets of miR-506, and that miR-506 can inhibit [[CDK4]]/6-[[FOXM1]] signalling, which is activated in the majority of serous ovarian carcinomas. This newly recognized miR-506-[[CDK4]]/6-[[FOXM1]] axis provides further insight into the pathogenesis of ovarian carcinoma and identifies a potential novel therapeutic agent.
|mesh-terms=* 3' Untranslated Regions
* Binding Sites
* Cell Line, Tumor
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase 6
* Female
* Forkhead Box Protein M1
* Forkhead Transcription Factors
* Gene Expression Regulation, Neoplastic
* Genotype
* Humans
* MicroRNAs
* Neoplasms, Cystic, Mucinous, and Serous
* Ovarian Neoplasms
* Phenotype
* Signal Transduction
* Time Factors
* Transfection
|keywords=* FOXM1
* miR-506
* ovarian carcinoma
* proliferation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144705
}}
{{medline-entry
|title=Expression profiling of cell cycle genes in human pancreatic islets with and without type 2 diabetes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23707792
|abstract=Microarray gene expression data were used to analyze the expression pattern of cyclin, cyclin-dependent kinase (CDKs) and cyclin-dependent kinase inhibitor (CDKIs) genes from human pancreatic islets with and without type 2 diabetes (T2D). Of the cyclin genes, [[CCNI]] was the most expressed. Data obtained from microarray and qRT-PCR showed higher expression of [[CCND1]] in diabetic islets. Among the CDKs, [[CDK4]], [[CDK8]] and [[CDK9]] were highly expressed, while [[CDK1]] was expressed at low level. High expression of [[[[CDK1]]8]] was observed in diabetic islets. Of the CDKIs, [[CDKN1A]] expression was higher in diabetic islets in both microarray and qRT-PCR. Expression of [[CDKN1A]], [[[[CDKN2A]]]], [[CCNI]]2, [[CDK3]] and [[CDK1]]6 was correlated with age. Finally, eight SNPs in these genes were associated with T2D in the DIAGRAM database. Our data provide a comprehensive expression pattern of cell cycle genes in human islets. More human studies are required to confirm and reproduce animal studies. 
|mesh-terms=* Aged
* Aging
* Case-Control Studies
* Cells, Cultured
* Cyclin-Dependent Kinase Inhibitor Proteins
* Cyclin-Dependent Kinases
* Cyclins
* Diabetes Mellitus, Type 2
* Female
* Gene Expression Profiling
* Genes, cdc
* Genetic Association Studies
* Genetic Predisposition to Disease
* Humans
* Insulin
* Insulin Secretion
* Islets of Langerhans
* Male
* Middle Aged
* Oligonucleotide Array Sequence Analysis
* Polymorphism, Single Nucleotide
* Transcriptome

|full-text-url=https://sci-hub.do/10.1016/j.mce.2013.05.003
}}
{{medline-entry
|title=Oxidized low-density lipoprotein induces hematopoietic stem cell senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23620010
|abstract=We have investigated oxidized low-density lipoprotein (ox-LDL) induced senescence in hematopoietic stem cells (HCs). Mouse Sca-1  HCs were separated and purified using the magnetic activated cell sorting technique. Ox-LDL induced significant senescence in HCs measured by SA-β-Gal staining, and reduced CFU-Mix colony-forming capacity, arresting cells at G0/G1 phase. In agreement with the cell cycle arrest, ox-LDL markedly reduced the expression of [[CDK4]], cyclin D, and cyclin E. As possible contributing factors for cell senescence, ox-LDL also induced cellular oxidative stress and reduced telomerase activity. 
|mesh-terms=* Animals
* Biomarkers
* Bone Marrow Cells
* Cellular Senescence
* Cyclin D
* Cyclin E
* Cyclin-Dependent Kinase 4
* Female
* Flow Cytometry
* G1 Phase Cell Cycle Checkpoints
* Gene Expression
* Hematopoietic Stem Cells
* Lipoproteins, LDL
* Male
* Mice
* Oxidative Stress
* Primary Cell Culture
* Telomerase
* beta-Galactosidase
|keywords=* aging
* hematopoietic stem cells
* oxidized low-density lipoprotein
|full-text-url=https://sci-hub.do/10.1002/cbin.10121
}}
{{medline-entry
|title=Effect of extracts from Radix Ginseng, Radix Notoginseng and Rhizoma Chuanxiong on delaying aging of vascular smooth muscle cells in aged rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22855034
|abstract=To observe the effect of extracts from Radix Ginseng, Radix Notoginseng and Rhizoma Chuanxiong (EXT) on delaying vascular smooth muscle cells (VSMCs) aging in aged rats. VSMCs were obtained by the modified tissue explants technique and were shown to be positive for smooth muscle α-actin (SM-α-actin) by immunohistochemistry staining. VSMCs obtained from the young rats were served as the young control group; VSMCs obtained from the old rats were treated with no drug (the old group), with low dose extracts (20 mg/L, the EXT low-concentration group) and high dose extracts (40 mg/L, the EXT high concentration group), and with Probucal (10(-6) mol/L, the Probucal group) as a positive control. All groups were cultured for 24 h in the medium with 10% serum for 24 h followed by another 24 h in the serum-free medium. At the end of the 48-h culture, the following analyses were performed including determination of senescence-associated β-galactosidase (SAβ-Gal) activity, flow cytometry analysis of cell cycle, real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) analyses of p16, Cyclin D1, cyclin-dependent kinase 4 ([[CDK4]]) and retinoblastoma (Rb) mRNA expression, and Western blotting analyses of p16, cyclin D1, [[CDK4]] and phosphoretinoblastoma (pRb) protein expressions. (1) In comparison to the younger rats, VSMCs from aged rats had significantly more SAβ-Gal positive cells (P<0.01) and more cells in S phase (P<0.05). VSMCs from the all treated groups showed a significant decrease in both SAβ-Gal positive cells (P<0.05) and S phase (P<0.05) compared to the old rats. (2) Compared with the young group, VSMCs in the old group had a significant decrease in p16 and Rb mRNA expression and a significant increase in Cyclin D1 and [[CDK4]] mRNA expression. Compared with the old group, VSMCs in the treated groups had a significant increase in p16 and Rb mRNA expression and a significant decrease in Cyclin D1 and [[CDK4]] mRNA expression (P<0.05). (3) Compared with the young group, VSMCs in the old group had a significant decrease in p16 protein expression and a significant increase in Cyclin D1, [[CDK4]] and pRb protein expressions (P<0.05). Compared with the old group, VSMCs in the treated groups had a significant increase in p16 protein expression and a significant decrease in cyclinD1, [[CDK4]] and pRb protein expressions (P<0.05). VSMCs obtained from old rats showed typical signs of cellular senescence and vascular aging. EXT had an effect on delaying senescence of VSMCs in vitro by altering the p16-cyclinD/CDK-Rb pathway.
|mesh-terms=* Aging
* Animals
* Aorta
* Cell Cycle
* Cellular Senescence
* Cyclin D1
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase Inhibitor p16
* Drugs, Chinese Herbal
* Flow Cytometry
* Gene Expression Regulation
* Male
* Muscle, Smooth, Vascular
* Myocytes, Smooth Muscle
* Panax
* Plant Extracts
* RNA, Messenger
* Rats
* Rats, Wistar
* Retinoblastoma Protein
* beta-Galactosidase

|full-text-url=https://sci-hub.do/10.1007/s11655-012-1180-1
}}
{{medline-entry
|title=The Wnt inhibitory factor 1 ([[WIF1]]) is targeted in glioblastoma and has a tumor suppressing function potentially by induction of senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21642372
|abstract=Gene expression-based prediction of genomic copy number aberrations in the chromosomal region 12q13 to 12q15 that is flanked by [[MDM2]] and [[CDK4]] identified Wnt inhibitory factor 1 ([[WIF1]]) as a candidate tumor suppressor gene in glioblastoma. [[WIF1]] encodes a secreted Wnt antagonist and was strongly downregulated in most glioblastomas as compared with normal brain, implying deregulation of Wnt signaling, which is associated with cancer. [[WIF1]] silencing was mediated by deletion (7/69, 10%) or epigenetic silencing by promoter hypermethylation (29/110, 26%). Co-amplification of [[MDM2]] and [[CDK4]] that is present in 10% of glioblastomas was associated in most cases with deletion of the whole genomic region enclosed, including the [[WIF1]] locus. This interesting pathogenetic constellation targets the RB and p53 tumor suppressor pathways in tandem, while simultaneously activating oncogenic Wnt signaling. Ectopic expression of [[WIF1]] in glioblastoma cell lines revealed a dose-dependent decrease of Wnt pathway activity. Furthermore, [[WIF1]] expression inhibited cell proliferation in vitro, reduced anchorage-independent growth in soft agar, and completely abolished tumorigenicity in vivo. Interestingly, [[WIF1]] overexpression in glioblastoma cells induced a senescence-like phenotype that was dose dependent. These results provide evidence that [[WIF1]] has tumor suppressing properties. Downregulation of [[WIF1]] in 75% of glioblastomas indicates frequent involvement of aberrant Wnt signaling and, hence, may render glioblastomas sensitive to inhibitors of Wnt signaling, potentially by diverting the tumor cells into a senescence-like state.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aging
* Animals
* Blotting, Western
* Brain Neoplasms
* Cell Adhesion
* Cell Line, Tumor
* Cell Proliferation
* DNA Methylation
* Down-Regulation
* Epigenesis, Genetic
* Female
* Gene Expression Regulation, Neoplastic
* Genes, Tumor Suppressor
* Glioblastoma
* Humans
* Immunoenzyme Techniques
* Mice
* Mice, Nude
* Promoter Regions, Genetic
* RNA, Messenger
* RNA, Small Interfering
* Repressor Proteins
* Reverse Transcriptase Polymerase Chain Reaction

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3129269
}}
{{medline-entry
|title=Requirement of Cdk4 for v-Ha-ras-Induced Breast Tumorigenesis and Activation of the v-ras-Induced Senescence Program by the R24C Mutation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20634902
|abstract=Activating mutations in [[CDK4]] and inactivation of its key kinase inhibitor, p16INK4A, have been implicated in the genesis and progression of human cancer. Previous work has demonstrated that [[CDK4]] expression is required for Neu-induced but not Wnt-induced breast tumorigenesis in mice. However, the role that [[CDK4]] plays in ras-mediated breast tumor development is not well defined. To gain an understanding of the role of Cdk4 in ras-induced breast tumorigenesis, MMTV-v-Ha-ras transgenic mice were bred with Cdk4( /neo) and Cdk4(R24C/R24C) mice to generate Cdk4(neo/neo):MMTV-v-Ha-ras, Cdk4( / ):MMTV-v-Ha-ras, and Cdk4(R24C/R24C):MMTV-v-Ha-ras mice. The studies presented here demonstrate that Cdk4 expression is essential for Ras-mediated breast tumorigenesis. Surprisingly, the results also show that coexpression of mutant ras and Cdk4R24C genes in breast epithelial cells leads to an activation of senescent pathways that delay tumorigenesis. Analysis of the phosphorylated form of [[H2AX]], a marker for DNA damage, indicated its increased presence in the tumors of Cdk4(R24C/R24C):MMTV-v-Ha-ras mice. These observations indicate that the increased apoptosis and senescence seen in breast tumors of these mice might be due to increased DNA damage response in cells expressing activated forms of ras and Cdk4(R24C).

|keywords=* Cdk4
* Ras
* apoptosis
* breast cancer
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904236
}}
{{medline-entry
|title=Growth hormone corrects proliferation and transcription of phosphoenolpyruvate carboxykinase in livers of old mice via elimination of CCAAT/enhancer-binding protein alpha-Brm complex.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/17107955
|abstract=Growth hormone (GH), which is reduced with age, corrects the impaired proliferative capacity of livers of old animals. In this paper, we present a mechanism by which GH eliminates age-dependent negative control of proliferation and increases transcription of liver-specific genes in livers of old mice. The reduced proliferative capacities of the liver of old animals are associated with the CCAAT/enhancer-binding protein alpha (C/EBPalpha)-Brm complex, which inhibits E2F-dependent promoters. We found that a sequestration of C/EBPalpha into complexes with Brm leads to a weak interaction of C/EBPalpha with promoters of liver-specific genes, expression of which is reduced in old animals. Injection of either GH or the regulator of the amplitude of endogenous GH release, ghrelin, reduces the C/EBPalpha-Brm complex in livers of old mice, leading to a derepression of E2F targets, to increased interactions of C/EBPalpha with promoters of liver-specific genes, and to correction of their expression. GH-dependent elimination of the complex is mediated by the inhibition of cyclin D3-[[CDK4]] activity and by elevation of a phosphatase, protein phosphatase 2A, which dephosphorylates C/EBPalpha and dissociates the complex.
|mesh-terms=* Aging
* Animals
* Base Sequence
* CCAAT-Enhancer-Binding Protein-alpha
* Cell Division
* Cyclin D3
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase 6
* Cyclins
* Down-Regulation
* Forkhead Box Protein M1
* Forkhead Transcription Factors
* Gene Expression Regulation, Enzymologic
* Ghrelin
* Growth Hormone
* Liver
* Mice
* Molecular Sequence Data
* Peptide Hormones
* Phosphoenolpyruvate Carboxykinase (GTP)
* Phosphoprotein Phosphatases
* Phosphorylation
* Promoter Regions, Genetic
* Protein Phosphatase 2
* Transcription Factors
* Transcription, Genetic

|full-text-url=https://sci-hub.do/10.1074/jbc.M608226200
}}
{{medline-entry
|title=D-type cyclins and G1 progression during liver development in the rat.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/15809057
|abstract=Initiation and progression through G1 requires the activity of signaling complexes containing cyclins (D- or E-type) and cyclin-dependent kinases ([[CDK4]]/6 and [[CDK2]], respectively). We set out to identify the G1-phase cyclins and CDKs that are operative during late gestation liver development in the rat. This is a period during which hepatocytes show a high rate of proliferation that is, at least in part, independent of the mitogenic signaling pathways that are functional in mature hepatocytes. RNase protection assay and Western immunoblotting indicated that cyclin D1 is expressed at similar levels in fetal and adult liver. When cyclin D1 was induced after partial hepatectomy, its predominant CDK-binding partner was [[CDK4]]. In contrast, cyclins D2 and D3 predominated in fetal liver and were complexed with both [[CDK4]] and [[CDK6]]. Little [[CDK6]] protein was expressed in quiescent or regenerating adult liver. Cyclins E1 and E2 were both transcriptionally up-regulated in fetal liver. Activity of complexes containing cyclins E1 and E2 was higher in fetal liver, as was content of the cell cycle regulator, Rb. In fetal liver, Rb was highly phosphorylated at both cyclin D- and cyclin E-dependent sites. In conclusion, liver development is associated with a switch from cyclin D2/D3-containing complexes to cyclin D1:[[CDK4]] complexes. We speculate that the switch in D-type cyclins may be associated with the dependence on mitogenic signaling that develops as hepatocytes mature.
|mesh-terms=* Aging
* Animals
* Antibodies
* Cyclin D1
* Cyclin D2
* Cyclin D3
* Cyclin E
* Cyclin-Dependent Kinases
* Cyclins
* Female
* G1 Phase
* Gene Expression Regulation, Developmental
* Immunoprecipitation
* Liver
* Liver Regeneration
* Male
* Phosphorylation
* Pregnancy
* Protein Binding
* RNA, Messenger
* Rats

|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2005.03.042
}}
{{medline-entry
|title=Aging impairs induction of cyclin-dependent kinases and down-regulation of p27 in mouse CD4( ) cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/10612647
|abstract=To define the link between the early activation defects and the impaired proliferation response of cells from old mice, we characterized the influence of age on expression and activity of proteins that participate in cell-cycle regulation. We found that aging led to significant declines in the ability of mouse CD4( ) T cells to respond to CD3 and [[CD28]] stimuli by induction of the cyclin-dependent kinases [[CDK2]], [[CDK4]], and [[CDK6]], whether the defect was assessed by protein level or functional activity. Induction of [[CDK2]] activity was also impaired in cells from old mice that were activated with PMA plus ionomycin, stimuli that bypass the TCR/CD3 complex, or by CD3/[[CD28]] in the presence of IL-2, indicating that the age-related changes lie, at least in part, downstream of the enzymes activated by these stimuli. We also noted an impairment in the ability of CD4( ) cells from old mice to down-regulate the CDK inhibitor p27 after activation, but we found no change in induction of p21, an inhibitor of CDK that may also play other roles in cell-cycle control. Altered CDK activation is likely to mediate the age-related decline in T cell proliferation to polyclonal stimulation.
|mesh-terms=* Aging
* Animals
* Blood Platelets
* CD28 Antigens
* CD3 Complex
* CD4-Positive T-Lymphocytes
* CDC2-CDC28 Kinases
* Cell Cycle Proteins
* Cyclin-Dependent Kinase 2
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase 6
* Cyclin-Dependent Kinase Inhibitor p27
* Cyclin-Dependent Kinases
* Down-Regulation
* Enzyme Activation
* Enzyme Induction
* Enzyme Inhibitors
* Interleukin-2
* Isoantibodies
* Kinetics
* Lymphocyte Activation
* Mice
* Mice, Inbred BALB C
* Mice, Inbred C57BL
* Microtubule-Associated Proteins
* Protein-Serine-Threonine Kinases
* Proto-Oncogene Proteins
* Tetradecanoylphorbol Acetate
* Tumor Suppressor Proteins

|full-text-url=https://sci-hub.do/10.1006/cimm.1999.1573
}}
{{medline-entry
|title=Expressions and activities of cell cycle regulatory molecules during the transition from myocyte hyperplasia to hypertrophy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/9799664
|abstract=The role of cell cycle dependent molecules in controlling the switch from cardiac myocyte hyperplasia to hypertrophy remains unclear, although in the rat this process occurs between day 3 and 4 after birth. In this study we have determined (1) cell cycle profiles by fluorescence activated cell sorting (FACS); and (2) expressions, co-expressions and activities of a number of cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors by reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting and in vitro kinase assays in freshly isolated rat cardiac myocytes obtained from 2, 3, 4 and 5-day-old animals. The percentage of myocytes found in the S phase of the cell cycle decreased significantly during the transition from hyperplasia to hypertrophy (5.5, 3.5, 2.3 and 1.9% of cells in 2-, 3-, 4- and 5-day-old myocytes, respectively,P<0.05), concomitant with a significant increase in the percentage of G0/G1 phase cells. At the molecular level, the expressions and activities of G1/S and G2/M phase acting cyclins and CDKs were downregulated significantly during the transition from hyperplasia to hypertrophy, whereas the expressions and activities of G1 phase acting cyclins and CDKs were upregulated significantly during this transition. In addition, p21(CIP1)- and p27(KIP1)- associated CDK kinase activities remained relatively constant when histone H1 was used as a substrate, whereas phosphorylation of the retinoblastoma protein was upregulated significantly during the transition from hyperplasia to hypertrophy. Thus, there is a progressive and significant G0/G1 phase blockade during the transition from myocyte hyperplasia to hypertrophy. Whilst [[CDK2]] and cdc2 may be pivotal in the withdrawal of cardiac myocytes from the cell cycle, [[CDK4]] and [[CDK6]] may be critical for maintaining hypertrophic growth of the myocyte during development.
|mesh-terms=* 3T3 Cells
* Aging
* Animals
* Animals, Newborn
* Cardiomegaly
* Cell Cycle
* Cells, Cultured
* Cyclin A
* Cyclin D2
* Cyclin D3
* Cyclin-Dependent Kinases
* Cyclins
* Female
* Gene Expression Regulation, Developmental
* Heart
* Hyperplasia
* Male
* Mice
* Myocardium
* Rats
* Rats, Wistar
* Reverse Transcriptase Polymerase Chain Reaction

|full-text-url=https://sci-hub.do/10.1006/jmcc.1998.0808
}}
{{medline-entry
|title=Expression of second messenger- and cyclin-dependent protein kinases during postnatal development of rat heart.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/9620176
|abstract=During early postnatal development, cardiomyocytes, which comprise about 80% of ventricular mass and volume, become phenotypically developed to facilitate their contractile functions and terminally differentiated to grow only in size but not in cell number. These changes are due to the expression of contractile proteins as well as the regulation of intracellular signal transduction proteins. In this study, the expression patterns of several protein kinases involved in various cardiac functions and cell-cycle control were analyzed by Western blotting of ventricular extracts from 1-, 10-, 20-, 50-, and 365-day-old rats. The expression level of cAMP-dependent protein kinase was slightly decreased (20%) over the first year, whereas no change was detected in cGMP-dependent protein kinase I. Calmodulin-dependent protein kinase II, which is involved in Ca2  uptake into the sarcoplasmic reticulum, was increased as much as ten-fold. To the contrary, the expressions of protein kinase C-alpha and iota declined 77% with age. Cyclin-dependent protein kinases (CDKs) such as [[CDK1]], [[CDK2]], [[CDK4]], and [[CDK5]], which are required for cell-cycle progression, abruptly declined to almost undetectable levels after 10-20 days of age. In contrast, other CDK-related kinases, such as [[CDK8]] or Kkialre, did not change significantly or increased up to 50% with age, respectively. Protein kinases implicated in CDK regulation such as [[CDK7]] and Wee1 were either slightly increased in expression or did not change significantly. All of the proteins that were detected in ventricular extracts were also identified in isolated cardiac myocytes in equivalent amounts and analyzed for their relative expression in ten other adult rat tissues.
|mesh-terms=* Aging
* Amino Acid Sequence
* Animals
* Blotting, Western
* Calcium-Calmodulin-Dependent Protein Kinase Type 2
* Calcium-Calmodulin-Dependent Protein Kinases
* Cell Cycle Proteins
* Cell Extracts
* Cyclic Nucleotide-Regulated Protein Kinases
* Cyclin-Dependent Kinases
* Heart Ventricles
* Male
* Molecular Sequence Data
* Myocardium
* Nuclear Proteins
* Organ Specificity
* Protein Kinase C
* Protein-Tyrosine Kinases
* Rats
* Rats, Sprague-Dawley
* Second Messenger Systems

|full-text-url=https://sci-hub.do/10.1002/(sici)1097-4644(19980615)69:4<506::aid-jcb11>3.0.co;2-6
}}