Редактирование: CDKN1A

Cyclin-dependent kinase inhibitor 1 (CDK-interacting protein 1) (Melanoma differentiation-associated protein 6) (MDA-6) (p21) [CAP20] [CDKN1] [CIP1] [MDA6] [PIC1] [SDI1] [WAF1]

==Publications==

{{medline-entry
|title=Contribution of senescence in human endometrial stromal cells during proliferative phase to embryo receptivity†.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32285109
|abstract=Successful assisted reproductive technology pregnancy depends on the viability of embryos and endometrial receptivity. However, the literature has neglected effects of the endometrial environment during the proliferative phase on implantation success or failure. Human endometrial stromal cells (hESCs) were isolated from endometrial tissues sampled at oocyte retrieval during the proliferative phase from women undergoing infertility treatment. Primary hESC cultures were used to investigate the relationship between stemness and senescence induction in this population and embryo receptivity. Patients were classified as receptive or non-receptive based on their pregnancy diagnosis after embryo transfer. Biomarkers of cellular senescence and somatic stem cells were compared between each sample. hESCs from non-receptive patients exhibited significantly higher (P < 0.01) proportions of senescent cells, mRNA expressions of [[[[CDKN2A]]]] and [[CDKN1A]] transcripts (P < 0.01), and expressions of genes encoding the senescence-associated secretory phenotype (P < 0.05). hESCs from receptive patients had significantly higher (P < 0.01) mRNA expressions of [[ABCG2]] and [[ALDH1A1]] transcripts. Our findings suggest that stemness is inversely associated with senescence induction in hESCs and, by extension, that implantation failure in infertility treatment may be attributable to a combination of senescence promotion and disruption of this maintenance function in this population during the proliferative phase of the menstrual cycle. This is a promising step towards potentially improving the embryo receptivity of endometrium. The specific mechanism by which implantation failure is prefigured by a loss of stemness among endometrial stem cells, and cellular senescence induction among hESCs, should be elucidated in detail in the future.

|keywords=* cellular senescence
* embryo receptivity
* endometrial stem cell
* human endometrial stromal cell
* infertility
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313258
}}
{{medline-entry
|title=Involvement of [[CDKN1A]] (p21) in cellular senescence in response to heat and irradiation stress during preimplantation development.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32253738
|abstract=This study examined the role of cyclin-dependent kinase inhibitor 1a (CDK1A, p21) in response to exogenous stressors during mouse preimplantation embryo development. [[CDKN1A]] knockdown (KD) one-cell zygotes were exposed to 39 °C heat stress (HS) for 4 days or irradiated by 1 (1-Gy) or 3 (3-Gy) Gy X-rays, and their developmental competence and gene expression were compared with control embryos. [[CDKN1A]] KD and HS did not influence early cleavage or subsequent embryonic development; however, HS delayed cavitation and induced elevated Cdkn1a expression in control embryos. Exposure to 1- or 3-Gy had no effect on development to the morula stage; however, a significant number of morulae failed to develop to the blastocyst stage. Interestingly, under the 1-Gy condition, the blastocyst rate of [[CDKN1A]] KD embryos (77.7%) was significantly higher than that of the controls (44.4%). In summary, exposure to cellular stressors resulted in the upregulation of Cdkn1a in embryos exposed to HS or X-ray irradiation, particularly in response to heat stress or low-dose X-ray irradiation, and depleting Cdkn1a mRNA alleviated cell cycle arrest. These findings suggest that [[CDKN1A]] plays a vital role in cellular senescence during preimplantation embryo development.

|keywords=* Cdkn1a
* Heat stress
* Irradiation
* Preimplantation
* Senescence
* p21
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193008
}}
{{medline-entry
|title=Candesartan Neuroprotection in Rat Primary Neurons Negatively Correlates with Aging and Senescence: a Transcriptomic Analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31811565
|abstract=Preclinical experiments and clinical trials demonstrated that angiotensin II AT  receptor overactivity associates with aging and cellular senescence and that AT  receptor blockers (ARBs) protect from age-related brain disorders. In a primary neuronal culture submitted to glutamate excitotoxicity, gene set enrichment analysis (GSEA) revealed expression of several hundred genes altered by glutamate and normalized by candesartan correlated with changes in expression in Alzheimer's patient's hippocampus. To further establish whether our data correlated with gene expression alterations associated with aging and senescence, we compared our global transcriptional data with additional published datasets, including alterations in gene expression in the neocortex and cerebellum of old mice, human frontal cortex after age of 40, gene alterations in the Werner syndrome, rodent caloric restriction, Ras and oncogene-induced senescence in fibroblasts, and to tissues besides the brain such as the muscle and kidney. The most significant and enriched pathways associated with aging and senescence were positively correlated with alterations in gene expression in glutamate-injured neurons and, conversely, negatively correlated when the injured neurons were treated with candesartan. Our results involve multiple genes and pathways, including [[CAV1]], [[CCND1]], [[CDKN1A]], [[CHEK1]], [[ICAM1]], IL-1B, IL-6, [[MAPK14]], [[PTGS2]], [[SERPINE1]], and [[TP53]], encoding proteins associated with aging and senescence hallmarks, such as inflammation, oxidative stress, cell cycle and mitochondrial function alterations, insulin resistance, genomic instability including telomere shortening and DNA damage, and the senescent-associated secretory phenotype. Our results demonstrate that AT  receptor blockade ameliorates central mechanisms of aging and senescence. Using ARBs for prevention and treatment of age-related disorders has important translational value.

|keywords=* Aging
* Angiotensin receptor blockers
* Glutamate excitotoxicity
* Senescence
* p53 neuroprotection
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062590
}}
{{medline-entry
|title=Identification of reference genes for RT-qPCR data normalisation in aging studies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31562345
|abstract=Aging is associated with changes in gene expression levels that affect cellular functions and predispose to age-related diseases. The use of candidate genes whose expression remains stable during aging is required to correctly address the age-associated variations in expression levels. Reverse transcription quantitative-polymerase chain reaction (RT-qPCR) has become a powerful approach for sensitive gene expression analysis. Reliable RT-qPCR assays rely on the normalisation of the results to stable reference genes. Taken these data together, here we evaluated the expression stability of eight frequently used reference genes in three aging models: oncogene-induced senescence (OIS), in vitro and in vivo aging. Using NormFinder and geNorm algorithms, we identified that the most stable reference gene pairs were [[PUM1]] and [[TBP]] in OIS, [[GUSB]] and [[PUM1]] for in vitro aging and [[GUSB]] and [[OAZ1]] for in vivo aging. To validate these candidates, we used them to normalise the expression data of [[CDKN1A]], [[APOD]] and [[TFRC]] genes, whose expression is known to be affected during OIS, in vitro and in vivo aging. This study demonstrates that accurate normalisation of RT-qPCR data is crucial in aging research and provides a specific subset of stable reference genes for future aging studies.
|mesh-terms=* Aging
* Algorithms
* Gene Expression Profiling
* Genes, Essential
* Humans
* Real-Time Polymerase Chain Reaction
* Software

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764958
}}
{{medline-entry
|title=Chromatin remodeling factor [[BAZ1A]] regulates cellular senescence in both cancer and normal cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31085244
|abstract=Cellular senescence is a well-known cancer prevention mechanism, inducing cancer cells to senescence can enhance cancer immunotherapy. However, how cellular senescence is regulated is not fully understood. Dynamic chromatin changes have been discovered during cellular senescence, while the causality remains elusive. [[BAZ1A]], a gene coding the accessory subunit of ATP-dependent chromatin remodeling complex, showed decreased expression in multiple cellular senescence models. We aim to investigate the functional role of [[BAZ1A]] in regulating senescence in cancer and normal cells. Knockdown of [[BAZ1A]] was performed via lentivirus mediated short hairpin RNA (shRNA) in various cancer cell lines (A549 and U2OS) and normal cells (HUVEC, NIH3T3 and MEF). A series of senescence-associated phenotypes were quantified by [[CCK]]-8 assay, SA-β-Gal staining and EdU incorporation assay, etc. KEY FINDINGS: Knockdown (KD) of [[BAZ1A]] induced series of senescence-associated phenotypes in both cancer and normal cells. [[BAZ1A]]-KD caused the upregulated expression of [[SMAD3]], which in turn activated the transcription of p21 coding gene [[CDKN1A]] and resulted in senescence-associated phenotypes in human cancer cells (A549 and U2OS). Our results revealed chromatin remodeling modulator [[BAZ1A]] acting as a novel regulator of cellular senescence in both normal and cancer cells, indicating a new target for potential cancer treatment.
|mesh-terms=* A549 Cells
* Animals
* Bone Neoplasms
* Cells, Cultured
* Cellular Senescence
* Chromatin Assembly and Disassembly
* Chromosomal Proteins, Non-Histone
* Fibroblasts
* Human Umbilical Vein Endothelial Cells
* Humans
* Mice
* NIH 3T3 Cells
* Osteosarcoma
* Signal Transduction
* Transcription Factors
|keywords=* BAZ1A
* Chromatin remodeling factor
* SMAD3
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2019.05.023
}}
{{medline-entry
|title=Histone demethylase [[KDM6B]] regulates 1,25-dihydroxyvitamin D3-induced senescence in glioma cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30825201
|abstract=Vitamin D is a fat-soluble vitamin and plays an important role in calcium absorption and bone development, whose lack can cause a variety of diseases, including cancer. Human epidemiological studies suggested that vitamin D3 deficiency might increase glioma incidence, but molecular mechanism is less understood. In this study, we show that 1,25-dihydroxyvitamin D3 (the active form of vitamin D3) induces senescence of glioma cells and increases the expression of senescence markers, INK4A and cyclin-dependent kinase inhibitor 1A ([[CDKN1A]]). 1,25-Dihydroxyvitamin D3 also upregulates the expression of histone demethylase, [[KDM6B]]. Knockdown of [[KDM6B]] attenuates 1,25-dihydroxyvitamin D3-induced senescence and upregulation of INK4A and [[CDKN1A]]. [[KDM6B]] promotes the transcription of INK4A by eliminating the trimethylation of repressive marker H3K27me3 near its promoter. This study reveals a new regulatory mechanism involved in vitamin D3 inhibition on gliomas, which is beneficial to prevention and adjuvant therapy of glioma.
|mesh-terms=* Antineoplastic Agents
* Brain Neoplasms
* Calcitriol
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* DNA Methylation
* Epigenesis, Genetic
* Gene Expression Regulation, Enzymologic
* Gene Expression Regulation, Neoplastic
* Glioma
* Humans
* Jumonji Domain-Containing Histone Demethylases
* Promoter Regions, Genetic
* Signal Transduction
|keywords=* 1,25-dihydroxyvitamin D3
* KDM6B
* glioma
* histone demethylase
* senescence
|full-text-url=https://sci-hub.do/10.1002/jcp.28431
}}
{{medline-entry
|title=A Novel [i]Dnmt3a1[/i] Transcript Inhibits Adipogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30333755
|abstract=[i]DNA (cytosine-5)-methyltransferase 3a[/i] ([i]Dnmt3a[/i]) is an enzyme that catalyzes the transfer of methyl groups to specific CpG forms in DNA. In mammals, two variant transcripts of [i]Dnmt3a[/i] have been successfully identified. To the best of our knowledge, no [i]Dnmt3a[/i] transcripts in an avian have been successfully identified. This study was performed to detect different transcripts of [i]Dnmt3a[/i] in chickens and to examine whether a novel [i]Dnmt3a[/i] transcript named [i]Dnmt3a1[/i] may regulate adipogenesis. In addition to cloning, sequencing, transcript detection, and expression studies, a novel [i]Dnmt3a1[/i] transcript overexpression and knockdown were conducted to explore the potential role of [i]Dnmt3a1[/i] in preadipocyte proliferation and the early stage of adipocyte differentiation. In chicken abdominal fat tissue, we detected a novel [i]Dnmt3a1[/i] transcript that differs from [i]Dnmt3a[/i] by lacking 23 amino acids at the exon-1/exon-2 border. [i]Dnmt3a1[/i] mRNA was ubiquitously expressed in a variety of tissues or cells and highly expressed in chicken adipose tissue/cells. The expression of [i]Dnmt3a1[/i] was regulated under different physiological conditions including aging, fasting, and high-fat diet. In addition, overexpression of [i]Dnmt3a1[/i] significantly decreased preadipocyte proliferation and induced cell-cycle arrest while its inhibition increased cell proliferation and S-phase cells. Furthermore, the overexpression of [i]Dnmt3a1[/i] significantly upregulated the mRNA level of cell-cycle-related genes, such as [i][[CDKN1A]][/i], [i][[CDKN1B]][/i], [i]CCNB3[/i], [i]CCND2[/i], [i][[CCNG2]][/i], [i]CDKN2B[/i], and [i]CDK9[/i], or the protein level of [[CDKN1A]], [[CDKN1B]], and [[CCNG2]]. Conversely, the knockdown of [i]Dnmt3a1[/i] by siRNA had the opposite effects. Moreover, during early adipocyte differentiation, the overexpression of [i]Dnmt3a1[/i] significantly decreased the mRNA and the protein levels of PPAR-γ, C/EBP-α, [[ADIPOR1]], and [[STAT3]], and the mRNA levels of [i]FAS[/i], [i]LEPR[/i], [i]LPL[/i], [i]PRKAB2[/i], and [i]ATGL.[/i] In contrast, their expression was significantly increased after the knockdown of [i]Dnmt3a1[/i]. Taken together, we identified a novel transcript of [i]Dnmt3a[/i], and it played a potential role in adipogenesis.

|keywords=* Dnmt3a
* Dnmt3a1 transcript
* aging
* early differentiation
* expression
* high-fat diet
* preadipocytes proliferation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176318
}}
{{medline-entry
|title=Altered modulation of lamin A/C-[[HDAC2]] interaction and p21 expression during oxidative stress response in HGPS.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30109767
|abstract=Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson-Gilford progeria, a severe [[LMNA]]-linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of [[CDKN1A]], encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with [[HDAC2]], an histone deacetylase that regulates [[CDKN1A]] expression. In control skin fibroblasts, lamin A/C is part of a protein complex including [[HDAC2]] and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by [[LMNA]]mutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C-[[HDAC2]] interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and [[HDAC2]] to cellular and organism aging. The lamin A/C-[[HDAC2]] complex may be a novel therapeutic target to slow down progression of progeria symptoms.
|mesh-terms=* Adolescent
* Aged
* Cells, Cultured
* Child
* Child, Preschool
* Cyclin-Dependent Kinase Inhibitor p21
* DNA Damage
* DNA Repair
* Female
* Fibroblasts
* Gene Expression Regulation
* Histone Deacetylase 2
* Humans
* Lamin Type A
* Male
* Mutation
* Oxidative Stress
* Progeria
* Protein Binding
* Substrate Specificity
|keywords=* CDKN1A (p21WAF1/Cip1)
* Hutchinson-Gilford progeria syndrome (HGPS)
* aging
* histone deacetylase 2 (HDAC2)
* lamin A/C
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156291
}}
{{medline-entry
|title=Conditioned medium from stimulated macrophages inhibits growth but induces an inflammatory phenotype in breast cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29966967
|abstract=Disparate roles exist for tumor-associated macrophages in breast cancer growth and progression. The aim of this study was to explore the influence of induced macrophages on the growth of breast cancer cells. THP-1 monocytes were differentiated to macrophages using phorbol 12-myristate 13-acetate. The effect of the medium from THP-1 monocytes or macrophage-conditioned medium (MφCM) on MCF-7 (estrogen receptor and progesterone-positive positive) and MDA-[[MB]]-231 ([[MB]]; triple-negative) breast cancer cells was determined at 24 h, 48 h and 72 h. Assays were conducted for cell viability, apoptosis, proliferation and cell phenotype, and quantitative real-time polymerase chain reaction (qRT-PCR) for expression of associated genes. MφCM inhibited proliferation of MCF-7 and [[MB]] cells in a time-dependent manner and, in particular, decreased viability of MCF-7 cells. MφCM induced a markedly vacuolated phenotype in MCF-7 increased apoptosis in MCF-7 cells, but correlative changes in Bcl-2 or Bax were absent. A multifold and significant reduction in anti-apoptotic Bcl-2 in [[MB]] cells was not matched by increased apoptosis. The cell cycle inhibitor [[CDKN1A]] was increased in both cell lines, but [[PCNA]] decreased only in [[MB]] cells. Senescence-associated galactosidase beta-1 (GLB1) mRNA was decreased in MCF-7 cells (48 and 72 h) but increased in [[MB]] cells (72 h). Increased expression of interleukin-6 (IL-6) and IL-8 was seen in both cell lines, and increased tumor necrosis factor- α was seen at 24 h for [[MB]] and 72 h for MCF-7 indicating increased inflammatory responses of the cancer cells. The two breast cancer celllines had different responses to MφCM, mainly involving inhibition rather than stimulation of growth of the cells, stimulation of senescence ([[MB]] cells) and increased inflammatory cytokine expression. The estrogen and progesterone receptor status of the cell lines may determine their response to MφCM. The function of the inflammatory cytokines in breast cancer growth remains to be identified.
|mesh-terms=* Apoptosis
* Apoptosis Regulatory Proteins
* Breast Neoplasms
* Cell Cycle Proteins
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Culture Media, Conditioned
* Cytokines
* Female
* Gene Expression Regulation, Neoplastic
* Humans
* Inflammation Mediators
* MCF-7 Cells
* Macrophage Activation
* Macrophages
* Paracrine Communication
* Phenotype
* Signal Transduction
* THP-1 Cells
* Tetradecanoylphorbol Acetate
* Time Factors
* Triple Negative Breast Neoplasms
|keywords=* Apoptosis
* Autophagy
* Breast cancer
* Inflammation
* Macrophage
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.biopha.2018.06.126
}}
{{medline-entry
|title=DNA damage and neurodegenerative phenotypes in aged Ciz1 null mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29154038
|abstract=Cell-cycle dysfunction and faulty DNA repair are closely intertwined pathobiological processes that may contribute to several neurodegenerative disorders. [[CDKN1A]] interacting zinc finger protein 1 ([[CIZ1]]) plays a critical role in DNA replication and cell-cycle progression at the G1/S checkpoint. Germline or somatic variants in [[CIZ1]] have been linked to several neural and extra-neural diseases. Recently, we showed that germline knockout of Ciz1 is associated with motor and hematological abnormalities in young adult mice. However, the effects of [[CIZ1]] deficiency in much older mice may be more relevant to understanding age-related declines in cognitive and motor functioning and age-related neurologic disorders such as isolated dystonia and Alzheimer disease. Mouse embryonic fibroblasts from Ciz1  mice showed abnormal sensitivity to the effects of γ-irradiation with persistent DNA breaks, aberrant cell-cycle progression, and apoptosis. Aged (18-month-old) Ciz1  mice exhibited marked deficits in motor and cognitive functioning, and, in brain tissues, overt DNA damage, NF-κB upregulation, oxidative stress, vascular dysfunction, inflammation, and cell death. These findings indicate that the deleterious effects of [[CIZ1]] deficiency become more pronounced with aging and suggest that defects of cell-cycle control and associated DNA repair pathways in postmitotic neurons could contribute to global neurologic decline in elderly human populations. Accordingly, the G1/S cell-cycle checkpoint and associated DNA repair pathways may be targets for the prevention and treatment of age-related neurodegenerative processes.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Brain
* Cell Cycle
* Cells, Cultured
* Cognition
* Cognitive Aging
* DNA Damage
* DNA Repair
* Female
* Fibroblasts
* Genes, cdc
* Male
* Mice
* Molecular Targeted Therapy
* NF-kappa B
* Neurodegenerative Diseases
* Nuclear Proteins
* Oxidative Stress
* Phenotype
|keywords=* Aging
* Apoptosis
* CIZ1
* Cell cycle
* DNA damage
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877805
}}
{{medline-entry
|title=Cellular Senescence in Mouse Hippocampus After Irradiation and the Role of p53 and p21.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28340115
|abstract=Diverse stress signals including irradiation may trigger cellular senescence. We asked whether irradiation induced senescence in mouse hippocampus, and whether p53 or p21 played a role in this response. Following whole-brain irradiation, polymerase chain reaction (PCR) arrays for senescence-associated genes showed increased expression of [[CDKN1A]] (p21) and [[[[CDKN2A]]]] (p19ARF) in mouse hippocampus at 9 weeks. Upregulation of p21 and p19ARF was confirmed using real-time PCR, which also demonstrated increased [[[[CDKN2A]]]]/p16INKa expression after irradiation. No altered regulation of another 17 senescence-associated genes was observed after irradiation. Immunohistochemistry revealed increased nuclear expression of p16INK4A, p19ARF, p53, p21, phosphorylated p38 (pp38), 4-hydroxy-2-nonenal, and interleukin-6 ([[IL6]]) in granule cells of dentate gyrus after irradiation. Increased p16 nuclear immunoreactivity was further observed in type -1 cells, the putative neural stem cells. γ-phosphorylated-histone-2A nuclear foci were also seen in dentate gyrus 9 weeks postirradiation. In nonirradiated mice knockout of the TRP53 or p21 gene, there was increased p16INK4A, p19ARF, and [[IL6]], but not pp38 in dentate gyrus. We conclude that irradiation induces transcript and protein expression profile alterations in mouse dentate gyrus consistent with the senescence phenotype. Absence of p53 or p21 results in increase in baseline expression of senescence markers with no further increase in expression after irradiation.
|mesh-terms=* Animals
* Biomarkers
* Cell Nucleus
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* Dentate Gyrus
* Hippocampus
* Interleukin-6
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Neural Stem Cells
* Up-Regulation
|keywords=* Cellular senescence
* Hippocampus
* Irradiation
* Neural stem cells
* PCR array
* p21
* p53
|full-text-url=https://sci-hub.do/10.1093/jnen/nlx006
}}
{{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=Establishment and application of a novel patient-derived KIAA1549:[[BRAF]]-driven pediatric pilocytic astrocytoma model for preclinical drug testing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28002790
|abstract=Pilocytic astrocytoma (PA) is the most frequent pediatric brain tumor. Activation of the MAPK pathway is well established as the oncogenic driver of the disease. It is most frequently caused by KIAA1549:[[BRAF]] fusions, and leads to oncogene induced senescence (OIS). OIS is thought to be a major reason for growth arrest of PA cells in vitro and in vivo, preventing establishment of PA cultures. Hence, valid preclinical models are currently very limited, but preclinical testing of new compounds is urgently needed. We transduced the PA short-term culture DKFZ-BT66 derived from the PA of a 2-year old patient with a doxycycline-inducible system coding for Simian Vacuolating Virus 40 Large T Antigen (SV40-TAg). SV40-TAg inhibits [[TP53]]/[[CDKN1A]] and [[[[CDKN2A]]]]/RB1, two pathways critical for OIS induction and maintenance. DNA methylation array and KIAA1549:[[BRAF]] fusion analysis confirmed pilocytic astrocytoma identity of DKFZ-BT66 cells after establishment. Readouts were analyzed in proliferating as well as senescent states, including cell counts, viability, cell cycle analysis, expression of SV40-Tag, [[[[CDKN2A]]]] (p16), [[CDKN1A]] (p21), and [[TP53]] (p53) protein, and gene-expression profiling. Selected MAPK inhibitors (MAPKi) including clinically available MEK inhibitors (MEKi) were tested in vitro. Expression of SV40-TAg enabled the cells to bypass OIS and to resume proliferation with a mean doubling time of 45h allowing for propagation and long-term culture. Withdrawal of doxycycline led to an immediate decrease of SV40-TAg expression, appearance of senescent morphology, upregulation of CDKI proteins and a subsequent G1 growth arrest in line with the re-induction of senescence. DKFZ-BT66 cells still underwent replicative senescence that was overcome by [[TERT]] expression. Testing of a set of MAPKi revealed differential responses in DKFZ-BT66. MEKi efficiently inhibited MAPK signaling at clinically achievable concentrations, while [[BRAF]] V600E- and RAF Type II inhibitors showed paradoxical activation. Taken together, we have established the first patient-derived long term expandable PA cell line expressing the KIAA1549:[[BRAF]]-fusion suitable for preclinical drug testing.
|mesh-terms=* Antigens, Polyomavirus Transforming
* Astrocytoma
* Blotting, Western
* Brain Neoplasms
* Cell Culture Techniques
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Child, Preschool
* Drug Screening Assays, Antitumor
* Gene Expression Profiling
* Humans
* Male
* Oncogene Proteins, Fusion
* Polymerase Chain Reaction
* Proto-Oncogene Proteins B-raf
* Transcriptome
* Transduction, Genetic
|keywords=* KIAA1549:BRAF-fusion
* MAPK-inhibitors
* oncogene-induced senescence (OIS)
* pediatric low grade glioma
* pilocytic astrocytoma
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355278
}}
{{medline-entry
|title=Phosphorylation of [[MITF]] by AKT affects its downstream targets and causes [[TP53]]-dependent cell senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27702651
|abstract=Microphthalmia-associated transcription factor ([[MITF]]) plays a crucial role in the melanogenesis and proliferation of melanocytes that is dependent on its abundance and modification. Here, we report that epidermal growth factor ([[EGF]]) induces senescence and cyclin-dependent kinase inhibitor 1A ([[CDKN1A]]) expression that is related to [[MITF]]. We found that [[MITF]] could bind [[TP53]] to regulate [[CDKN1A]]. Furthermore, the interaction between [[MITF]] and [[TP53]] is dependent on AKT activity. We found that AKT phosphorylates [[MITF]] at S510. Phosphorylated [[MITF]] S510 enhances its affinity to [[TP53]] and promotes [[CDKN1A]] expression. Meanwhile, the unphosphorylative [[MITF]] promotes [[TYR]] expression. The levels of p-[[MITF]]-S510 are low in 90% human melanoma samples. Thus the level of p-[[MITF]]-S510 could be a possible diagnostic marker for melanoma. Our findings reveal a mechanism for regulating [[MITF]] functions in response to [[EGF]] stimulation and suggest a possible implementation for preventing the over proliferation of melanoma cells.
|mesh-terms=* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* Gene Expression Regulation, Neoplastic
* Humans
* Inhibitor of Differentiation Proteins
* Melanoma
* Microphthalmia-Associated Transcription Factor
* Phosphorylation
* Proteolysis
* Proto-Oncogene Proteins c-akt
* Tumor Suppressor Protein p53
|keywords=* AKT
* MITF
* Phosphorylation
* Senescence
* TP53
|full-text-url=https://sci-hub.do/10.1016/j.biocel.2016.09.029
}}
{{medline-entry
|title=Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26809688
|abstract=Human respiratory syncytial virus (HRSV) accounts for the majority of lower respiratory tract infections during infancy and childhood and is associated with significant morbidity and mortality. HRSV provokes a proliferation arrest and characteristic syncytia in cellular systems such as immortalized epithelial cells. We show here that HRSV induces the expression of DNA damage markers and proliferation arrest such as P-[[TP53]], P-[[ATM]], [[CDKN1A]] and γH2AFX in cultured cells secondary to the production of mitochondrial reactive oxygen species (ROS). The DNA damage foci contained γH2AFX and [[[[TP53]]BP1]], indicative of double-strand breaks (DSBs) and could be reversed by antioxidant treatments such as N-Acetylcysteine (NAC) or reduced glutathione ethyl ester (GSHee). The damage observed is associated with the accumulation of senescent cells, displaying a canonical senescent phenotype in both mononuclear cells and syncytia. In addition, we show signs of DNA damage and aging such as γH2AFX and [[[[CDKN2A]]]] expression in the respiratory epithelia of infected mice long after viral clearance. Altogether, these results show that HRSV triggers a DNA damage-mediated cellular senescence program probably mediated by oxidative stress. The results also suggest that this program might contribute to the physiopathology of the infection, tissue remodeling and aging, and might be associated to long-term consequences of HRSV infections.
|mesh-terms=* A549 Cells
* Acetylcysteine
* Animals
* Cell Line
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p18
* DNA Breaks, Double-Stranded
* DNA Damage
* Glutathione
* Histones
* Host-Pathogen Interactions
* Humans
* Mice
* Oxidative Stress
* Reactive Oxygen Species
* Respiratory Mucosa
* Respiratory Syncytial Virus Infections
* Respiratory Syncytial Virus, Human
|keywords=* DNA damage
* ROS
* cellular senescence
* human respiratory
* syncytial virus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871660
}}
{{medline-entry
|title=Docosahexaenoic acid prevented tumor necrosis factor alpha-induced endothelial dysfunction and senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26802937
|abstract=We investigated how docosahexaenoic acid (DHA) regulated tumor necrosis factor-alpha ([[TNF]]-α)-induced senescence and dysfunction in endothelial cells (EC). We used RT-PCR to examine the expression of several genes related to senescence and dysfunction in EC. [[TNF]]-α-induced p21 protein levels were investigated by Western blot (WB) and fluorescence antibody techniques. [[TNF]]-α induced the senescence marker β-galactosidase and the expression of several senescence and endothelial dysfunction-related genes, e.g., [[CDKN1A]], [[SHC1]] and [[GLB1]]. DHA attenuated [[TNF]]-α-induced senescence-related gene expression and p21 protein expression. DHA attenuated [[TNF]]-α-induced gene expression related to dysfunction of EC, such as plasminogen activator inhibitor 1 (SERPINE1), lectin-like oxidized low-density lipoprotein receptor-1 (OLR1), thromboxane A2 receptor (TXA2R) and p38 MAPK (MAPK14). DHA reversed the [[TNF]]-α-mediated reduction of endothelial nitric oxide synthase (NOS3) gene expression. [[TNF]]-α-mediated upregulation of these genes was inhibited by allopurinol and apocynin. These results indicated that DHA regulated the expression of several genes that are associated with senescence and dysfunction of EC. 
|mesh-terms=* Cell Line
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* Docosahexaenoic Acids
* Endothelial Cells
* Humans
* Nitric Oxide Synthase Type III
* Plasminogen Activator Inhibitor 1
* Scavenger Receptors, Class E
* Shc Signaling Adaptor Proteins
* Src Homology 2 Domain-Containing, Transforming Protein 1
* Tumor Necrosis Factor-alpha
* beta-Galactosidase
|keywords=* DHA
* Dysfunction
* Endothelial cells
* Senescence
* TNFα
|full-text-url=https://sci-hub.do/10.1016/j.plefa.2015.10.006
}}
{{medline-entry
|title=TP53inp1 Gene Is Implicated in Early Radiation Response in Human Fibroblast Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26512655
|abstract=Tumor protein 53-induced nuclear protein-1 (TP53inp1) is expressed by activation via p53 and p73. The purpose of our study was to investigate the role of TP53inp1 in response of fibroblasts to ionizing radiation. γ-Ray radiation dose-dependently induces the expression of TP53inp1 in human immortalized fibroblast (F11hT) cells. Stable silencing of TP53inp1 was done via lentiviral transfection of shRNA in F11hT cells. After irradiation the clonogenic survival of TP53inp1 knockdown (F11hT-shTP) cells was compared to cells transfected with non-targeting (NT) shRNA. Radiation-induced senescence was measured by SA-β-Gal staining and autophagy was detected by Acridine Orange dye and microtubule-associated protein-1 light chain 3 (LC3B) immunostaining. The expression of TP53inp1, GDF-15, and [[CDKN1A]] and alterations in radiation induced mitochondrial DNA deletions were evaluated by qPCR. TP53inp1 was required for radiation (IR) induced maximal elevation of [[CDKN1A]] and GDF-15 expressions. Mitochondrial DNA deletions were increased and autophagy was deregulated following irradiation in the absence of TP53inp1. Finally, we showed that silencing of TP53inp1 enhances the radiation sensitivity of fibroblast cells. These data suggest functional roles for TP53inp1 in radiation-induced autophagy and survival. Taken together, we suppose that silencing of TP53inp1 leads radiation induced autophagy impairment and induces accumulation of damaged mitochondria in primary human fibroblasts. 
|mesh-terms=* Autophagy
* Carrier Proteins
* Cell Line
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* DNA, Mitochondrial
* Fibroblasts
* Growth Differentiation Factor 15
* Heat-Shock Proteins
* Humans
|keywords=* CDKN1A
* GDF-15
* RNA interference
* TP53inp1
* autophagy
* p53-network
* radiosensitivity
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632809
}}
{{medline-entry
|title=Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25963977
|abstract=The tumor suppressor p53 is a major regulator of genes important for cell cycle arrest, senescence, apoptosis, and innate immunity, and has recently been implicated in retinal aging. In this study we sought to identify the genetic networks that regulate p53 function in the retina using quantitative trait locus (QTL) analysis. First we examined age-associated changes in the activation and expression levels of p53; known p53 target proteins and markers of innate immune system activation in primary retinal pigment epithelial ([[RPE]]) cells that were harvested from young and aged human donors. We observed increased expression of p53, activated caspase-1, [[CDKN1A]], [[[[CDKN2A]]]] (p16INK4a), [[TLR4]], and IFNα in aged primary [[RPE]] cell lines. We used the Hamilton Eye Institute (HEI) retinal dataset ( www.genenetwork.org ) to identify genomic loci that modulate expression of genes in the p53 pathway in recombinant inbred BXD mouse strains using a QTL systems biology-based approach. We identified a significant trans-QTL on chromosome 1 (region 172-177 Mb) that regulates the expression of Cdkn1a. Many of the genes in this QTL locus are involved in innate immune responses, including Fc receptors, interferon-inducible family genes, and formin 2. Importantly, we found an age-related increase in [[FCGR3A]] and [[FMN2]] and a decrease in [[IFI16]] levels in [[RPE]] cultures. There is a complex multigenic innate immunity locus that controls expression of genes in the p53 pathway in the [[RPE]], which may play an important role in modulating age-related changes in the retina.
|mesh-terms=* Adult
* Aged, 80 and over
* Aging
* Animals
* Apoptosis
* Caspases
* Caspases, Initiator
* Cell Line
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* Gene Expression Regulation
* Humans
* Immunity, Innate
* Interferon-alpha
* Interferon-gamma
* Mice
* Mice, Inbred BALB C
* Mice, Inbred C57BL
* Mice, Inbred DBA
* Primary Cell Culture
* Quantitative Trait Loci
* Retinal Pigment Epithelium
* Signal Transduction
* Toll-Like Receptor 4
* Tumor Suppressor Protein p53

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450138
}}
{{medline-entry
|title=Tocotrienol-rich fraction prevents cellular aging by modulating cell proliferation signaling pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25945449
|abstract=Vitamin E has been suggested as nutritional intervention for the prevention of degenerative and age-related diseases. In this study, we aimed to elucidate the underlying mechanism of tocotrienol-rich fraction (TRF) in delaying cellular aging by targeting the proliferation signaling pathways in human diploid fibroblasts (HDFs). Tocotrienol-rich fraction was used to treat different stages of cellular aging of primary human diploid fibroblasts viz. young (passage 6), pre-senescent (passage 15) and senescent (passage 30). Several selected targets involved in the downstream of PI3K/AKT and RAF/MEK/ERK pathways were compared in total RNA and protein. Different transcriptional profiles were observed in young, pre-senescent and senescent HDFs, in which cellular aging increased AKT, [[FOXO3]], [[CDKN1A]] and RSK1 mRNA expression level, but decreased [[ELK1]], [[FOS]] and [[SIRT1]] mRNA expression level. With tocotrienol-rich fraction treatment, gene expression of AKT, [[FOXO3]], ERK and RSK1 mRNA was decreased in senescent cells, but not in young cells. The three down-regulated mRNA in cellular aging, [[ELK1]], [[FOS]] and [[SIRT1]], were increased with tocotrienol-rich fraction treatment. Expression of [[FOXO3]] and P21Cip1 proteins showed up-regulation in senescent cells but tocotrienol-rich fraction only decreased P21Cip1 protein expression in senescent cells. Tocotrienol-rich fraction exerts gene modulating properties that might be responsible in promoting cell cycle progression during cellular aging.
|mesh-terms=* Antioxidants
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Diploidy
* Fibroblasts
* Humans
* Tocotrienols
* Vitamin E
|keywords=* Cellular aging
* Gene expression
* Human diploid fibroblasts
* Tocotrienol-rich fraction
* Vitamin E
|full-text-url=https://sci-hub.do/10.7417/CT.2015.1825
}}
{{medline-entry
|title=Orphan nuclear receptor TLX functions as a potent suppressor of oncogene-induced senescence in prostate cancer via its transcriptional co-regulation of the [[CDKN1A]] (p21(WAF1) (/) (CIP1) ) and SIRT1 genes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25557355
|abstract=Oncogene-induced senescence is an important tumour-suppressing mechanism to prevent both premalignant transformation and cancer progression. Overcoming this process is a critical step in early cancer development. The druggable orphan nuclear receptor TLX (NR2E1) is characterized as an important regulator of neural stem cells and is also implicated in the development of some brain tumours. However, its exact functional roles in cancer growth regulation still remain unclear. Here we report that TLX can act as a promoter of tumourigenesis in prostate cancer by suppressing oncogene-induced senescence. We determined that TLX exhibited an increased expression in high-grade prostate cancer tissues and many prostate cancer cell lines. Functional studies revealed that TLX could perform an oncogenic function in prostate cancer cells, as its knockdown triggered cellular senescence and cell growth arrest in vitro and in vivo, whereas its over-expression promoted the malignant growth of prostate cancer cells. Furthermore, enhancement of TLX activity, by either ectopic expression or ligand stimulation, could potently prevent doxorubicin-induced senescence in prostate cancer cells and also allow prostatic epithelial cells to escape oncogene-induced senescence induced either by activated oncogene H-Ras(G12V) or knockdown of tumour suppressor PTEN, via a mechanism of direct but differential transcriptional regulation of two senescence-associated genes, repression of [[CDKN1A]] and transactivation of SIRT1. Together, our present study shows, for the first time, that TLX may play an important role in prostate carcinogenesis through its suppression of oncogene-induced senescence, and also suggests that targeting the senescence-regulatory TLX is of potential therapeutic significance in prostate cancer.
|mesh-terms=* Animals
* Cell Proliferation
* Cell Transformation, Neoplastic
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* Gene Expression Regulation
* Humans
* Male
* Mice, SCID
* PTEN Phosphohydrolase
* Prostatic Neoplasms
* Receptors, Cytoplasmic and Nuclear
* Sirtuin 1
|keywords=* SIRT1
* TLX
* nuclear receptor
* oncogene-induced senescence
* p21
* prostate cancer
|full-text-url=https://sci-hub.do/10.1002/path.4505
}}
{{medline-entry
|title=Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24626178
|abstract=Non-alcohol-related fatty liver disease (NAFLD) encompasses a wide spectrum, ranging from steatosis alone to steatohepatitis and fibrosis. Presence of steatohepatitis and fibrosis are key hallmarks of disease progression. Previous studies have demonstrated an association between hepatocyte p21 expression and fibrosis stage in NAFLD. The aim of this study is to investigate the association between the variants of [[CDKN1A]], which encodes p21, and disease progression in NAFLD. To this end, the relation between [[CDKN1A]] polymorphism and liver fibrosis was studied in 2 cohorts of biopsy-proven NAFLD patients from UK (n = 323) and Finland (n = 123). Genotyping was performed using DNA isolated from lymphocytes collected at the time of liver biopsy. The findings of the UK cohort were tested in the Finnish cohort. Both the UK and Finnish cohorts were significantly different from each other in basic demographics. In the UK cohort, rs762623, of the 6 SNPs across [[CDKN1A]] tested, was significantly associated with disease progression in NAFLD. This association was confirmed in the Finnish cohort. Despite the influence on fibrosis development, SNPs across [[CDKN1A]] did not affect the progression of liver fibrosis. In conclusion, [[CDKN1A]] variant rs762623 is associated with the development but not the propagation of progressive liver disease in NAFLD. 
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Biomarkers
* Cellular Senescence
* Cohort Studies
* Cyclin-Dependent Kinase Inhibitor p21
* Disease Progression
* England
* Female
* Finland
* Genetic Association Studies
* Humans
* Liver Cirrhosis
* Male
* Middle Aged
* Non-alcoholic Fatty Liver Disease
* Polymorphism, Single Nucleotide
* Young Adult
|keywords=* cell cycle inhibitor p21
* chronic liver disease
* liver fibrosis
* polymorphism
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050146
}}
{{medline-entry
|title=Id4 promotes senescence and sensitivity to doxorubicin-induced apoptosis in DU145 prostate cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24122992
|abstract=Inhibitor of differentiation proteins (Id1, 2, 3 and 4) are dominant negative regulators of basic helix loop helix transcription factors and play dominant roles in cancer cells, spanning several molecular pathways including senescence, invasion, metastasis, proliferation and apoptosis. In contrast to high Id1, Id2 and Id3 expression, the expression of Id4 is epigenetically silenced in prostate cancer. In the present study we demonstrated a novel role of Id4, that of promotion of cellular senescence in prostate cancer cells. Id4 was ectopically expressed in DU145 cells (DU145 Id4). The cells treated with Doxorubicin (0-500 nm) or vehicle control were analyzed for apoptosis, senescence (SA-beta Galactosidase), and expression of [[CDKN1A]] (p21), CDKN1B(p27), [[[[CDKN2A]]]] (p16), [[E2F1]], vimentin and E-cadherin by immuno-histochemistry and/or Western blot. In the present study we demonstrated that Id4 promotes cellular senescence in prostate cancer cell line DU145. Ectopic overexpression of Id4 in androgen receptor-negative DU145 prostate cancer cells resulted in increased expression of p16, p21, p27, E-cadherin and vimentin but down-regulated [[E2F1]] expression. Id4 also potentiated the effect of doxorubicin induced senescence and apoptosis. The absence of functional p16, pRB and p53 in DU145 suggests that Id4 could alter additional molecular pathways such as those involving [[E2F1]] to promote senescence and increased sensitivity to doxorubicin-induced apoptosis. The results of the present study support the role of Id4 as a tumor suppressor in prostate cancer.
|mesh-terms=* Antibiotics, Antineoplastic
* Antigens, CD
* Apoptosis
* Cadherins
* Cell Line, Tumor
* Cell Shape
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor Proteins
* Doxorubicin
* Drug Resistance, Neoplasm
* E2F1 Transcription Factor
* Gene Expression
* Gene Expression Regulation, Neoplastic
* Humans
* Inhibitor of Differentiation Proteins
* Male
* Prostatic Neoplasms
* Tumor Suppressor Proteins
* Vimentin
|keywords=* DU145
* E2F1
* Id4
* apoptosis
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042247
}}
{{medline-entry
|title=A molecular signature predictive of indolent prostate cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24027026
|abstract=Many newly diagnosed prostate cancers present as low Gleason score tumors that require no treatment intervention. Distinguishing the many indolent tumors from the minority of lethal ones remains a major clinical challenge. We now show that low Gleason score prostate tumors can be distinguished as indolent and aggressive subgroups on the basis of their expression of genes associated with aging and senescence. Using gene set enrichment analysis, we identified a 19-gene signature enriched in indolent prostate tumors. We then further classified this signature with a decision tree learning model to identify three genes--[[FGFR1]], [[PMP22]], and [[CDKN1A]]--that together accurately predicted outcome of low Gleason score tumors. Validation of this three-gene panel on independent cohorts confirmed its independent prognostic value as well as its ability to improve prognosis with currently used clinical nomograms. Furthermore, protein expression of this three-gene panel in biopsy samples distinguished Gleason 6 patients who failed surveillance over a 10-year period. We propose that this signature may be incorporated into prognostic assays for monitoring patients on active surveillance to facilitate appropriate courses of treatment.
|mesh-terms=* Aged
* Aging
* Animals
* Biomarkers, Tumor
* Decision Trees
* Gene Expression Profiling
* Gene Expression Regulation, Neoplastic
* Genes, Neoplasm
* Humans
* Male
* Mice
* Middle Aged
* Models, Biological
* Prognosis
* Prostatic Neoplasms
* RNA, Messenger
* Reproducibility of Results
* Species Specificity

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943244
}}
{{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=Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22882466
|abstract=In senescent cells, a DNA damage response drives not only irreversible loss of replicative capacity but also production and secretion of reactive oxygen species (ROS) and bioactive peptides including pro-inflammatory cytokines. This makes senescent cells a potential cause of tissue functional decline in aging. To our knowledge, we show here for the first time evidence suggesting that DNA damage induces a senescence-like state in mature postmitotic neurons in vivo. About 40-80% of Purkinje neurons and 20-40% of cortical, hippocampal and peripheral neurons in the myenteric plexus from old C57Bl/6 mice showed severe DNA damage, activated p38MAPkinase, high ROS production and oxidative damage, interleukin IL-6 production, heterochromatinization and senescence-associated β-galactosidase activity. Frequencies of these senescence-like neurons increased with age. Short-term caloric restriction tended to decrease frequencies of positive cells. The phenotype was aggravated in brains of late-generation TERC-/- mice with dysfunctional telomeres. It was fully rescued by loss of p21([[CDKN1A]]) function in late-generation TERC-/-[[CDKN1A]]-/- mice, indicating p21 as the necessary signal transducer between DNA damage response and senescence-like phenotype in neurons, as in senescing fibroblasts and other proliferation-competent cells. We conclude that a senescence-like phenotype is possibly not restricted to proliferation-competent cells. Rather, dysfunctional telomeres and/or accumulated DNA damage can induce a DNA damage response leading to a phenotype in postmitotic neurons that resembles cell senescence in multiple features. Senescence-like neurons might be a source of oxidative and inflammatory stress and a contributor to brain aging.
|mesh-terms=* Aging
* Animals
* Caloric Restriction
* Cell Count
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* DNA Damage
* Gene Expression Regulation, Developmental
* Humans
* Interleukin-6
* Mice
* Mice, Inbred C57BL
* Mitosis
* Myenteric Plexus
* Phenotype
* Purkinje Cells
* RNA
* Reactive Oxygen Species
* Signal Transduction
* Telomerase
* Telomere
* beta-Galactosidase
* p38 Mitogen-Activated Protein Kinases

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533793
}}
{{medline-entry
|title=Markers of cellular senescence in zero hour biopsies predict outcome in renal transplantation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/18462273
|abstract=Although chronological donor age is the most potent predictor of long-term outcome after renal transplantation, it does not incorporate individual differences of the aging-process itself. We therefore hypothesized that an estimate of biological organ age as derived from markers of cellular senescence in zero hour biopsies would be of higher predictive value. Telomere length and mRNA expression levels of the cell cycle inhibitors [[[[CDKN2A]]]] (p16INK4a) and [[CDKN1A]] (p21WAF1) were assessed in pre-implantation biopsies of 54 patients and the association of these and various other clinical parameters with serum creatinine after 1 year was determined. In a linear regression analysis, [[[[CDKN2A]]]] turned out to be the best single predictor followed by donor age and telomere length. A multiple linear regression analysis revealed that the combination of [[[[CDKN2A]]]] values and donor age yielded even higher predictive values for serum creatinine 1 year after transplantation. We conclude that the molecular aging marker [[[[CDKN2A]]]] in combination with chronological donor age predict renal allograft function after 1 year significantly better than chronological donor age alone.
|mesh-terms=* Adult
* Aging
* Biomarkers
* Biopsy
* Cellular Senescence
* Creatinine
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* Demography
* Female
* Humans
* Kidney
* Kidney Transplantation
* Male
* Middle Aged
* Postoperative Period
* Regression Analysis
* Telomere
* Time Factors
* Tissue Donors
* Transplantation, Homologous
* Treatment Outcome

|full-text-url=https://sci-hub.do/10.1111/j.1474-9726.2008.00398.x
}}