Редактирование: CDK6

Cyclin-dependent kinase 6 (EC 2.7.11.22) (Cell division protein kinase 6) (Serine/threonine-protein kinase PLSTIRE) [CDKN6]

==Publications==

{{medline-entry
|title=D-galactose induces senescence of glioblastoma cells through YAP-[[CDK6]] pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32991321
|abstract=Treatment of glioblastoma using radiotherapy and chemotherapy has various outcomes, key among them being cellular senescence. However, the molecular mechanisms of this process remain unclear. In the present study, we tested the ability of D-galactose (D-gal), a reducing sugar, to induce senescence in glioblastoma cells. Following pretreatment with D-gal, glioblastoma cell lines ([[C6]] and U87MG) showed typical characteristics of senescence. These included the reduced cell proliferation, hypertrophic morphology, increased senescence-associated β-galactosidase activity, downregulation of Lamin B1, and upregulation of several senescence-associated genes such as p16, p53, and NF-κB. Furthermore, our results showed that D-gal was more suitable than etoposide (a DNA-damage drug) in inducing senescence of glioblastoma cells. Mechanistically, D-gal inactivated the YAP-[[CDK6]] signaling pathway, while overexpression of YAP or [[CDK6]] could restore D-gal-induced senescence of [[C6]] cells. Finally, metformin, an anti-aging agent, activated the YAP-[[CDK6]] pathway and suppressed D-gal-induced senescence of [[C6]] cells. Taken together, these findings established a new model for analyzing senescence in glioblastoma cells, which occurred through the YAP-[[CDK6]] pathway. This is expected to provide a basis for development of novel therapies for the treatment of glioblastoma.

|keywords=* CDK6
* D-galatose
* YAP
* cellular senescence
* glioblastoma
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585072
}}
{{medline-entry
|title=Saturated Fatty Acids Promote Hepatocytic Senecence through Regulation of miR-34a/Cyclin-Dependent Kinase 6.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32970940
|abstract=Obesity increases intracellular lipid accumulation in hepatocytes, which can induce non-alcoholic fatty liver disease (NAFLD). With progression of NAFLD, a sizable fraction of patients develop non-alcoholic steatohepatitis (NASH), eventually leading to cirrhosis and hepatocellular carcinoma (HCC). The mechanism involved in obesity-induced NAFLD remains unclear. Free fatty acids and high-fat diets, which induce hepatocyte senescence, are major risk factors for NAFLD. Therefore in this study, the mechanism of lipotoxicity-induced hepatocyte senescence is investigated. The mice are fed a high-fat diet (HFD) and BNL CL.2 cells are treated with palmitate acid (PA) to establish in vivo and in vitro models of lipotoxicity, respectively. SA-β-gal staining is used to analyze the positively stained senescent hepatocytes. The results show that both PA and HFD induce cellular senescence. Real-time-PCR quantitative analysis reveals that miR-34a is significantly upregulated in the liver tissues of the HFD mice and in the PA-treated BNL CL.2 cells. Western blotting analysis shows that cyclin-dependent kinase inhibitor 1 (CDKN1, also known as p21) is upregulated, while cyclin-dependent kinase 6 ([[CDK6]]) is downregulated. Further investigation of the mechanism reveals that [[CDK6]] is a target of miR-34a, which binds to the 3' UTR of [[CDK6]] and inhibits its expression. The findings reveal that miR-34a is upregulated in a high-fat environment in the liver, and induces hepatocyte senescence by targeting [[CDK6]]. The miR-34a-[[CDK6]] signaling axis may promote NAFLD development in a high-fat environment and therefore represents a potential target for NAFLD therapy.

|keywords=* cyclin-dependent kinase 6 (CDK6)
* high-fat diet (HFD)
* miR-34a
* palmitate acid (PA)
* senescence
|full-text-url=https://sci-hub.do/10.1002/mnfr.202000383
}}
{{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=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=Palbociclib Effectively Halts Proliferation but Fails to Induce Senescence in Patient-Derived Glioma Stem Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31124078
|abstract=Glioblastoma multiforme is the most aggressive primary brain tumor. Current knowledge suggests that the growth and recurrence of these tumors are due in part to the therapy-resistant glioma stem cell subpopulation, which possesses the ability for self-renewal and proliferation, driving tumor progression. In many cancers, the p16 -CDK4/6-pRb pathway is disrupted in favor of cell cycle progression. In particular, the frequent deregulation of CDK4/6 in cancer positions these kinases as promising targets. Palbociclib, a potent and selective CDK4/6 inhibitor, has been approved by the FDA as a first-line treatment of advanced breast cancer and there is currently interest in evaluating its effect on other cancer types. Palbociclib has been reported to be efficient, not only at halting proliferation, but also at inducing senescence in different tumor types. In this study, we evaluated the effect of this inhibitor on four patient-derived glioma stem cell-enriched cell lines. We found that Palbociclib rapidly and effectively inhibits proliferation without affecting cell viability. We also established that in these cell lines [[CDK6]] is the key interphase CDK for controlling cell cycle progression. Prolonged exposure to Palbociclib induced a senescent-like phenotype characterized by flattened morphology, cell cycle arrest, increased β-galactosidase activity and induction of other senescent-associated markers. However, we found that after Palbociclib removal cell lines resumed normal proliferation, which implies they conserved their replicative potential. As a whole, our results indicate that in patient-derived glioma stem cell-enriched cell lines, Palbociclib induces a senescent-like quiescence rather than true senescence.
|mesh-terms=* Apoptosis
* Brain Neoplasms
* Cell Cycle Checkpoints
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase 6
* Fibroblasts
* Glioma
* Humans
* Neoplastic Stem Cells
* Phenotype
* Piperazines
* Pyridines
* Roscovitine
|keywords=* CDK4/6
* Glioma stem cells
* Palbociclib
* Quiescence
* Senescence
|full-text-url=https://sci-hub.do/10.1007/s12035-019-1633-z
}}
{{medline-entry
|title=Avenanthramide A Induces Cellular Senescence via miR-129-3p/Pirh2/p53 Signaling Pathway To Suppress Colon Cancer Growth.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30888162
|abstract=Cellular senescence is the state of irreversible cell cycle arrest that provides a blockade during oncogenic transformation and tumor development. Avenanthramide A (AVN A) is an active ingredient exclusively extracted from oats, which possesses antioxidant, anti-inflammatory, and anticancer activities. However, the underlying mechanism(s) of AVN A in the prevention of cancer progression remains unclear. In the current study, we revealed that AVN A notably attenuated tumor formation in an azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model. AVN A treatment triggered cellular senescence in human colon cancer cells, evidenced by enlarging cellular size, upregulating β-galactosidase activity, γ-[[H2AX]] positive staining, and G1 phase arrest. Moreover, AVN A treatment significantly increased the expression of miR-129-3p, which markedly repressed the E3 ubiquitin ligase Pirh2 and two other targets, [[IGF2BP3]] and [[CDK6]]. The Pirh2 silencing by miR-129-3p led to a significant increase in protein levels of p53 and its downstream target p21, which subsequently induced cell senescence. Taken together, our data indicate that miR-129-3p/Pirh2/p53 is a critical signaling pathway in AVN A induced cellular senescence and AVN A could be a potential chemopreventive strategy for cancer treatment.
|mesh-terms=* Animals
* Cell Cycle
* Cell Proliferation
* Cellular Senescence
* Colonic Neoplasms
* Cyclin-Dependent Kinase Inhibitor p21
* Down-Regulation
* Humans
* Male
* Mice
* Mice, Inbred C57BL
* MicroRNAs
* Promoter Regions, Genetic
* Signal Transduction
* Tumor Suppressor Protein p53
* Ubiquitin-Protein Ligases
* ortho-Aminobenzoates
|keywords=* Pirh2
* avenanthramide A
* cellular senescence
* colorectal cancer
* miR-129-3p
|full-text-url=https://sci-hub.do/10.1021/acs.jafc.9b00833
}}
{{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=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=G protein-coupled receptor kinase 4-induced cellular senescence and its senescence-associated gene expression profiling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28912086
|abstract=Senescent cells have lost their capacity for proliferation and manifest as irreversibly in cell cycle arrest. Many membrane receptors, including G protein-coupled receptors (GPCRs), initiate a variety of intracellular signaling cascades modulating cell division and potentially play roles in triggering cellular senescence response. GPCR kinases (GRKs) belong to a family of serine/threonine kinases. Although their role in homologous desensitization of activated GPCRs is well established, the involvement of the kinases in cell proliferation is still largely unknown. In this study, we isolated [[GRK4]]-GFP expressing HEK293 cells by fluorescence-activated cell sorting (FACS) and found that the ectopic expression of [[GRK4]] halted cell proliferation. Cells expressing [[GRK4]] ([[GRK4]]( )) demonstrated cell cycle G1/G0 phase arrest, accompanied with significant increase of senescence-associated-β-galactosidase (SA-β-Gal) activity. Expression profiling analysis of 78 senescence-related genes by qRT-PCR showed a total of 17 genes significantly changed in [[GRK4]]( ) cells (≥ 2 fold, p < 0.05). Among these, 9 genes - [[AKT1]], p16 , p27 , p19 , [[IGFBP3]], [[MAPK14]], [[PLAU]], [[THBS1]], [[TP73]] - were up-regulated, while 8 genes, Cyclin A2, Cyclin D1, [[CDK2]], [[CDK6]], [[ETS1]], [[NBN]], [[RB1]], [[SIRT1]], were down-regulated. The increase in cyclin-dependent kinase inhibitors (p16, p27) and p38 MAPK proteins ([[MAPK14]]) was validated by immunoblotting. Neither p53 nor p21  protein was detectable, suggesting no p53 activation in the HEK293 cells. These results unveil a novel function of [[GRK4]] on triggering a p53-independent cellular senescence, which involves an intricate signaling network.
|mesh-terms=* Cell Division
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Flow Cytometry
* G-Protein-Coupled Receptor Kinase 4
* Gene Expression Profiling
* Gene Expression Regulation
* HEK293 Cells
* Humans
* MCF-7 Cells
* Transcriptome
* Tumor Suppressor Protein p53
|keywords=* Cellular senescence
* G protein-coupled receptor kinase 4
* Gene expression profiling
* p53-independent senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944352
}}
{{medline-entry
|title=Genome-Wide Overexpression Screen Identifies Genes Able to Bypass p16-Mediated Senescence in Melanoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27872202
|abstract=Malignant melanomas often arise from nevi, which result from initial oncogene-induced hyperproliferation of melanocytes that are maintained in a CDKN2A/p16-mediated senescent state. Thus, genes that can bypass this senescence barrier are likely to contribute to melanoma development. We have performed a gain-of-function screen of 17,030 lentivirally expressed human open reading frames (ORFs) in a melanoma cell line containing an inducible p16 construct to identify such genes. Genes known to bypass p16-induced senescence arrest, including the human papilloma virus 18 E7 gene ( HPV18E7), and genes such as the p16-binding [[CDK6]] with expected functions, as well as panel of novel genes, were identified, including high-mobility group box (HMGB) proteins. A number of these were further validated in two other models of p16-induced senescence. Tissue immunohistochemistry demonstrated higher levels of [[CDK6]] in primary melanomas compared with normal skin and nevi. Reduction of [[CDK6]] levels drove melanoma cells expressing functional p16 into senescence, demonstrating its contribution to bypass senescence.
|mesh-terms=* Cell Cycle Checkpoints
* Cell Line, Tumor
* Cellular Senescence
* Cyclin-Dependent Kinase 6
* Cyclin-Dependent Kinase Inhibitor p16
* DNA-Binding Proteins
* Gene Expression Regulation, Neoplastic
* Gene Library
* Genetic Vectors
* Genome, Human
* HEK293 Cells
* HMGB Proteins
* High-Throughput Screening Assays
* Humans
* Lentivirus
* Melanocytes
* Melanoma
* Nevus
* Oncogene Proteins, Viral
* Open Reading Frames
* Skin Neoplasms
|keywords=* CDK6
* high-content imaging
* overexpression screening
* p16
* senescence
|full-text-url=https://sci-hub.do/10.1177/1087057116679592
}}
{{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=MicroRNA-33 promotes the replicative senescence of mouse embryonic fibroblasts by suppressing [[CDK6]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27059142
|abstract=MicroRNAs are a large class of tiny noncoding RNAs, which have emerged as critical regulators of gene expression, and thus are involved in multiple cellular processes, including cellular senescence. MicroRNA-33 has previously been established to exert crucial effect on cell proliferation, lipid metabolism and cholesterol metabolism. Nonetheless, the association between microRNA-33 and cellular senescence and its underlying molecular mechanism are far to be elucidated. The present study has attempted to probe into the effect of microRNA-33 on MEFs senescence. Our data unveiled that microRNA-33 was dramatically down-regulated in senescent MEFs compared to the young MEFs, and ectopic expression of microRNA-33 promoted MEFs senescence, while knock-down of microRNA-33 exhibited a protective effect against senescence phenotype. Moreover, we verified [[CDK6]] as a direct target of microRNA-33 in mouse. Silencing of [[CDK6]] induced the premature senescence phenotype of MEFs similarly as microRNA-33, while enforced expression of [[CDK6]] significantly reverse the senescence-induction effect of microRNA-33. Taken together, our results suggested that microRNA-33 enhanced the replicative senescence of MEFs potentially by suppressing [[CDK6]] expression.
|mesh-terms=* Animals
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Cyclin-Dependent Kinase 6
* Embryo, Mammalian
* Fibroblasts
* Male
* Mice
* Mice, Inbred C57BL
* MicroRNAs
|keywords=* CDK6
* Cellular senescence
* MicroRNA-33
* Proliferation
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2016.04.016
}}
{{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=Sporadic colorectal cancer development shows rejuvenescence regarding epithelial proliferation and apoptosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24098334
|abstract=Sporadic colorectal cancer (CRC) development is a sequential process showing age-dependency, uncontrolled epithelial proliferation and decreased apoptosis. During juvenile growth cellular proliferation and apoptosis are well balanced, which may be perturbed upon aging. Our aim was to correlate proliferative and apoptotic activities in aging human colonic epithelium and colorectal cancer. We also tested the underlying molecular biology concerning the proliferation- and apoptosis-regulating gene expression alterations. Colorectal biopsies from healthy children (n1 = 14), healthy adults (n2 = 10), adult adenomas (n3 = 10) and CRCs (n4 = 10) in adults were tested for Ki-67 immunohistochemistry and TUNEL apoptosis assay. Mitosis- and apoptosis-related gene expression was also studied in healthy children (n1 = 6), adult (n2 = 41) samples and in CRC (n3 = 34) in HGU133plus2.0 microarray platform. Measured alterations were confirmed with RT-PCR both on dependent and independent sample sets (n1 = 6, n2 = 6, n3 = 6). Mitotic index (MI) was significantly higher (p<0.05) in intact juvenile (MI = 0.33±0.06) and CRC samples (MI = 0.42±0.10) compared to healthy adult samples (MI = 0.15±0.06). In contrast, apoptotic index (AI) was decreased in children (0.13±0.06) and significantly lower in cancer (0.06±0.03) compared to healthy adult samples (0.17±0.05). Eight proliferation- (e.g. [[MKI67]], CCNE1) and 11 apoptosis-associated genes (e.g. [[TNFSF10]], IFI6) had altered mRNA expression both in the course of normal aging and carcinogenesis, mainly inducing proliferation and reducing apoptosis compared to healthy adults. Eight proliferation-associated genes including [[CCND1]], [[CDK1]], [[CDK6]] and 26 apoptosis-regulating genes (e.g. SOCS3) were differently expressed between juvenile and cancer groups mostly supporting the pronounced cell growth in CRC. Colorectal samples from children and CRC patients can be characterized by similarly increased proliferative and decreased apoptotic activities compared to healthy colonic samples from adults. Therefore, cell kinetic alterations during colorectal cancer development show uncontrolled rejuvenescence as opposed to the controlled cell growth in juvenile colonic epithelium.
|mesh-terms=* Adult
* Aging
* Apoptosis
* Carcinogenesis
* Cell Proliferation
* Child
* Colorectal Neoplasms
* Female
* Gene Expression Profiling
* Humans
* Intestinal Mucosa
* Male

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789736
}}
{{medline-entry
|title=Aging and microRNA expression in human skeletal muscle: a microarray and bioinformatics analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20876843
|abstract=A common characteristic of aging is loss of skeletal muscle (sarcopenia), which can lead to falls and fractures. MicroRNAs (miRNAs) are novel posttranscriptional modulators of gene expression with potential roles as regulators of skeletal muscle mass and function. The purpose of this study was to profile miRNA expression patterns in aging human skeletal muscle with a miRNA array followed by in-depth functional and network analysis. Muscle biopsy samples from 36 men [young: 31 ± 2 (n = 19); older: 73 ± 3 (n = 17)] were 1) analyzed for expression of miRNAs with a miRNA array, 2) validated with TaqMan quantitative real-time PCR assays, and 3) identified (and later validated) for potential gene targets with the bioinformatics knowledge base software Ingenuity Pathways Analysis. Eighteen miRNAs were differentially expressed in older humans (P < 0.05 and >500 expression level). Let-7 family members Let-7b and Let-7e were significantly elevated and further validated in older subjects (P < 0.05). Functional and network analysis from Ingenuity determined that gene targets of the Let-7s were associated with molecular networks involved in cell cycle control such as cellular proliferation and differentiation. We confirmed with real-time PCR that mRNA expression of cell cycle regulators [[CDK6]], [[CDC25A]], and [[CDC34]] were downregulated in older compared with young subjects (P < 0.05). In addition, [[PAX7]] mRNA expression was lower in older subjects (P < 0.05). These data suggest that aging is characterized by a higher expression of Let-7 family members that may downregulate genes related to cellular proliferation. We propose that higher Let-7 expression may be an indicator of impaired cell cycle function possibly contributing to reduced muscle cell renewal and regeneration in older human muscle.
|mesh-terms=* Adult
* Aged
* Aging
* Computational Biology
* Databases, Genetic
* Gene Expression
* Gene Expression Profiling
* Humans
* Male
* MicroRNAs
* Microarray Analysis
* Muscle, Skeletal
* Sequence Analysis, DNA

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110890
}}
{{medline-entry
|title=[Effect of Oviductus Ranae on Cyclin D1, [[CDK6]] and P15 expressions in the liver tissue of aged male rats].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20501390
|abstract=To investigate the effect of Oviductus Ranae (OR) on the expressions of CyclinD1, [[CDK6]] and P15 in the liver of aged male rats. Eighteen male SD rats were randomly divided into 3 equal groups, namely the OR group, VE group and ageing model group. The rats received subcutaneous injection of D-galactose for 6 weeks to establish the aging models, and another 6 rats were injected daily with normal saline (NS) to serve as the normal control group. From the third week of the experiment, the rats were given oral OR or Vitamin E (VE) accordingly till the sixth week. After completion of the drug administration, all the rats were sacrificed for detecting the expressions of CyclinD1, [[CDK6]] and P15 in the liver tissue by Western blotting. The relative expression levels of CyclinD1, [[CDK6]] and P15 in the liver of the rats in the OR group were 41.73-/ 0.54, 23.29-/ 0.30 and 1.49-/ 0.30, respectively, significantly up-regulated as compared with those in the ageing model group (P<0.01). The expressions of the proteins were obviously down-regulated in the model group in comparison with those in the normal control group. OR treatment can lower the expressions of Cyclin D1 and [[CDK6]] in the liver to enhance the liver cell proliferation in aged male rats. OR also promotes the expression of P15 through a feedback mechanism to prevent excessive proliferation of the cells. The effect of OR against ageing is mediated possibly by up-regulation of the proteins associated with the cell proliferation in the liver, a mechanism different from that of VE.
|mesh-terms=* Aging
* Animals
* Cyclin D1
* Cyclin-Dependent Kinase 6
* Cyclin-Dependent Kinase Inhibitor p15
* Liver
* Male
* Materia Medica
* Rats


}}
{{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
}}