Редактирование: CDKN2A

Tumor suppressor ARF (Alternative reading frame) (ARF) (Cyclin-dependent kinase inhibitor 2A) (p14ARF) [CDKN2] [MLM]

==Publications==

{{medline-entry
|title=Association between Nrf2 and [[[[CDKN2A]]]] expression in patients with end-stage renal disease: a pilot study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32661200
|abstract=Patients with end-stage renal disease (ESRD) display phenotypic features of premature biological aging, characterized by disproportionately high morbidity and mortality at a younger age. Nuclear factor erythroid 2-related factor 2 (Nrf2) activity, a master regulator of antioxidative responses, declines with age and is implicated in the pathogenesis of age-related disorders; however, little is known about the association between Nrf2 and premature biological aging in ESRD patients. In a cross-sectional pilot cohort of 34 ESRD patients receiving maintenance hemodialysis, we measured the expression of Nrf2 and cyclin-dependent kinase inhibitor 2A ([[[[CDKN2A]]]], or p16 , a biomarker of biological aging) genes in whole blood and examined the association of Nrf2 with [[[[CDKN2A]]]] expression, using Spearman's rank correlation and multivariable linear regression models with adjustment for potential confounders. There was a significant negative correlation between Nrf2 and [[[[CDKN2A]]]] expression (rho=-0.51, [i]P[/i]=0.002); while no significant correlation was found between Nrf2 expression and chronological age (rho=-0.02, [i]P[/i]=0.91). After multivariable adjustment, Nrf2 expression remained significantly and negatively associated with [[[[CDKN2A]]]] expression ([i]β[/i] coefficient=-1.51, [i]P[/i]=0.01), independent of chronological age, gender, race, and diabetes status. These findings suggest a potential contribution of Nrf2 dysfunction to the development of premature biological aging and its related morbidities in ESRD patients.

|keywords=* CDKN2A
* Nrf2
* aging
* end-stage renal disease
* inflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485736
}}
{{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=Chlorella vulgaris modulates the expression of senescence-associated genes in replicative senescence of human diploid fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31642042
|abstract=Human diploid fibroblasts (HDFs) cultured in vitro have limited capacity to proliferate after population doubling is repeated several times, and they enter into a state known as replicative senescence or cellular senescence. This study aimed to investigate the effect of Chlorella vulgaris on the replicative senescence of HDFs by determining the expression of senescence-associated genes. Young and senescent HDFs were divided into untreated control and C. vulgaris-treated groups. A senescence-associated gene transcription analysis was carried out with qRT-PCR. Treatment of young HDFs with C. vulgaris reduced the expression of [[SOD1]], [[CAT]] and [[CCS]] (p < 0.05). In addition, the expression of the [[SOD2]] gene was increased with C. vulgaris treatment in young, pre-senescent and senescent HDFs (p < 0.05). Treatment of senescent HDFs with C. vulgaris resulted in the downregulation of [[TP53]] gene expression. The expression of the [[[[CDKN2A]]]] gene was significantly decreased upon C. vulgaris treatment in young and senescent HDFs. C. vulgaris treatment was also found to significantly upregulate the expression of the [[MAPK14]] gene in pre-senescent HDFs. In addition, the expression of [[MAPK14]] was significantly upregulated compared to that in the untreated senescent HDFs (p < 0.05). In summary, the expression of senescence-associated genes related to antioxidants and the insulin/insulin-like growth factor-1 signalling, DNA damage-associated signalling, cell differentiation and cell proliferation pathways was modulated by C. vulgaris during replicative senescence of human diploid fibroblasts.
|mesh-terms=* Antioxidants
* Catalase
* Cell Differentiation
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Chlorella vulgaris
* DNA Damage
* Diploidy
* Fibroblasts
* Gene Expression
* Genes, p53
* Humans
* Male
* Mitogen-Activated Protein Kinase 14
* Molecular Chaperones
* Primary Cell Culture
* Signal Transduction
* Superoxide Dismutase
* Superoxide Dismutase-1
|keywords=* Chlorella vulgaris
* Fibroblasts
* Replicative senescence
* Senescence-associated genes
|full-text-url=https://sci-hub.do/10.1007/s11033-019-05140-8
}}
{{medline-entry
|title=Astrocyte senescence may drive alterations in GFAPα, [[[[CDKN2A]]]] p14 , and TAU3 transcript expression and contribute to cognitive decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31654269
|abstract=The accumulation of senescent cells in tissues is causally linked to the development of several age-related diseases; the removal of senescent glial cells in animal models prevents Tau accumulation and cognitive decline. Senescent cells can arise through several distinct mechanisms; one such mechanism is dysregulation of alternative splicing. In this study, we characterised the senescent cell phenotype in primary human astrocytes in terms of SA-β-Gal staining and SASP secretion, and then assessed splicing factor expression and candidate gene splicing patterns. Finally, we assessed associations between expression of dysregulated isoforms and premature cognitive decline in 197 samples from the InCHIANTI study of ageing, where expression was present in both blood and brain. We demonstrate here that senescent astrocytes secrete a modified SASP characterised by increased IL8, [[MMP3]], [[MMP10]], and [[TIMP2]] but decreased [[IL10]] levels. We identified significant changes in splicing factor expression for 10/20 splicing factors tested in senescent astrocytes compared with early passage cells, as well as dysregulation of isoform levels for 8/13 brain or senescence genes tested. Finally, associations were identified between peripheral blood GFAPα, TAU3, and [[[[CDKN2A]]]] (P14 ) isoform levels and mild or severe cognitive decline over a 3-7-year period. Our data are suggestive that some of the features of cognitive decline may arise from dysregulated splicing of important genes in senescent brain support cells, and that defects in alternative splicing or splicing regulator expression deserve exploration as points of therapeutic intervention in the future.
|mesh-terms=* Aged
* Alternative Splicing
* Astrocytes
* Cells, Cultured
* Cellular Senescence
* Cognitive Dysfunction
* Cytokines
* Gene Expression
* Glial Fibrillary Acidic Protein
* Humans
* Matrix Metalloproteinases
* Transcription, Genetic
* Tumor Suppressor Protein p14ARF
* tau Proteins
|keywords=* Alternative splicing
* Gene expression
* Neurodegenerative disease
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885035
}}
{{medline-entry
|title=Analysis of somatic mutations identifies signs of selection during in vitro aging of primary dermal fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31385397
|abstract=Somatic mutations are critical for cancer development and may play a role in age-related functional decline. Here, we used deep sequencing to analyze the prevalence of somatic mutations during in vitro cell aging. Primary dermal fibroblasts from healthy subjects of young and advanced age, from Hutchinson-Gilford progeria syndrome and from xeroderma pigmentosum complementation groups A and C, were first restricted in number and then expanded in vitro. DNA was obtained from cells pre- and post-expansion and sequenced at high depth (1656× mean coverage), over a cumulative 290 kb target region, including the exons of 44 aging-related genes. Allele frequencies of 58 somatic mutations differed between the pre- and post-cell culture expansion passages. Mathematical modeling revealed that the frequency change of three of the 58 mutations was unlikely to be explained by genetic drift alone, indicative of positive selection. Two of these three mutations, [[[[CDKN2A]]]] c.53C>T (T18M) and [[ERCC8]] c.*772T>A, were identified in cells from a patient with [[XPA]]. The allele frequency of the [[[[CDKN2A]]]] mutation increased from 0% to 55.3% with increasing cell culture passage. The third mutation, [[BRCA2]] c.6222C>T (H2074H), was identified in a sample from a healthy individual of advanced age. However, further validation of the three mutations suggests that other unmeasured variants probably provide the selective advantage in these cells. Our results reinforce the notions that somatic mutations occur during aging and that some are under positive selection, supporting the model of increased tissue heterogeneity with increased age.
|mesh-terms=* Adolescent
* Aged, 80 and over
* Cells, Cultured
* Cellular Senescence
* Child
* Child, Preschool
* DNA
* Female
* Fibroblasts
* Humans
* Male
* Mutation
* Sequence Analysis, RNA
* Skin
|keywords=* aging cell
* cell mosaicism
* genome instability
* molecular biology of aging
* positive selection
* somatic mutation
* tissue heterogeneity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826141
}}
{{medline-entry
|title=Analysis of the putative tumor suppressor gene cdkn2ab in pigment cells and melanoma of Xiphophorus and medaka.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30117276
|abstract=In humans, the [[[[CDKN2A]]]] locus encodes two transcripts, INK4A and ARF. Inactivation of either one by mutations or epigenetic changes is a frequent signature of malignant melanoma and one of the most relevant entry points for melanomagenesis. To analyze whether cdkn2ab, the fish ortholog of [[[[CDKN2A]]]], has a similar function as its human counterpart, we studied its action in fish models for human melanoma. Overexpression of cdkn2ab in a Xiphophorus melanoma cell line led to decreased proliferation and induction of a senescence-like phenotype, indicating a melanoma-suppressive function analogous to mammals. Coexpression of Xiphophorus cdkn2ab in medaka transgenic for the mitfa:xmrk melanoma-inducing gene resulted in full suppression of melanoma development, whereas CRISPR/Cas9 knockout of cdkn2ab resulted in strongly enhanced tumor growth. In summary, this provides the first functional evidence that cdkn2ab acts as a potent tumor suppressor gene in fish melanoma models.
|mesh-terms=* Animals
* Carcinogenesis
* Cyclin-Dependent Kinase Inhibitor p16
* Cyprinodontiformes
* Evolution, Molecular
* Gene Expression Regulation, Neoplastic
* Gene Knockout Techniques
* Genes, Tumor Suppressor
* Melanocytes
* Melanoma, Experimental
* Multigene Family
* Oryzias
* Phenotype
* Phylogeny
|keywords=* 
xmrk

* cell cycle regulation
* nevi
* p16/INK4A
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377863
}}
{{medline-entry
|title=In vitro behavior and UV response of melanocytes derived from carriers of [[[[CDKN2A]]]] mutations and [[MC1R]] variants.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30117292
|abstract=Coinheritance of germline mutation in cyclin-dependent kinase inhibitor 2A ([[[[CDKN2A]]]]) and loss-of-function (LOF) melanocortin 1 receptor ([[MC1R]]) variants is clinically associated with exaggerated risk for melanoma. To understand the combined impact of these mutations, we established and tested primary human melanocyte cultures from different [[[[CDKN2A]]]] mutation carriers, expressing either wild-type [[MC1R]] or [[MC1R]]LOF variant(s). These cultures expressed the [[[[CDKN2A]]]] product p16 (INK4A) and functional [[MC1R]]. Except for 32ins24 mutant melanocytes, the remaining cultures showed no detectable aberrations in proliferation or capacity for replicative senescence. Additionally, the latter cultures responded normally to ultraviolet radiation (UV) by cell cycle arrest, JNK, p38, and p53 activation, hydrogen peroxide generation, and repair of DNA photoproducts. We propose that malignant transformation of melanocytes expressing [[[[CDKN2A]]]] mutation and [[MC1R]]LOF allele(s) requires acquisition of somatic mutations facilitated by [[MC1R]] genotype or aberrant microenvironment due to [[[[CDKN2A]]]] mutation in keratinocytes and fibroblasts.
|mesh-terms=* Adolescent
* Adult
* Animals
* Cells, Cultured
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p15
* DNA Damage
* Female
* Genetic Predisposition to Disease
* Heterozygote
* Humans
* Male
* Melanocytes
* Mutation
* Neoplasm Proteins
* Phosphorylation
* Receptor, Melanocortin, Type 1
* Retinoblastoma Protein
* Ultraviolet Rays
* Young Adult
* beta-Galactosidase
|keywords=* CDKN2A
* MC1R
* proliferation
* replicative senescence
* ultraviolet radiation
|full-text-url=https://sci-hub.do/10.1111/pcmr.12732
}}
{{medline-entry
|title=Endothelial PPARγ (Peroxisome Proliferator-Activated Receptor-γ) Is Essential for Preventing Endothelial Dysfunction With Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29735632
|abstract=Little is known about mechanisms that control vascular aging, particularly at the cell-specific level. PPARγ (peroxisome proliferator-activated receptor-γ) exerts protective effects in the vasculature when activated pharmacologically. To gain insight into the cell-specific impact of PPARγ, we examined the hypothesis that genetic interference with endothelial PPARγ would augment age-induced vascular dysfunction. We studied carotid arteries from adult (11.6±0.3 months) and old (24.7±0.6 months) mice with endothelial-specific expression of a human dominant negative mutation in PPARγ driven by the vascular cadherin promoter (E-V290M), along with age-matched, nontransgenic littermates. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation in arteries from adult nontransgenic and E-V290M mice and old nontransgenic mice. In contrast, responses to acetylcholine were reduced by >50% in old male and female E-V290M mice ([i]P[/i]<0.01). Endothelial function in old E-V290M mice was not altered by an inhibitor of COX (cyclooxygenase) but was restored to normal by a superoxide scavenger, an inhibitor of NADPH oxidase, or inhibition of ROCK (Rho kinase). Relaxation of arteries to nitroprusside, which acts directly on vascular muscle, was similar in all groups. Vascular expression of IL (interleukin)-6, Nox-2, and [[[[CDKN2A]]]] (a marker of senescence) was significantly increased in old E-V290M mice compared with controls ([i]P[/i]<0.05). These findings provide the first evidence that age-related vascular dysfunction, inflammation, and senescence is accelerated after interference with endothelial PPARγ via mechanisms involving oxidative stress and ROCK. The finding of an essential protective role for endothelial PPARγ has implications for vascular disease and therapy for vascular aging.
|mesh-terms=* Aging
* Animals
* Carotid Arteries
* Disease Models, Animal
* Endothelium, Vascular
* Female
* Gene Expression Regulation
* Male
* Mice
* Mice, Inbred C57BL
* Oxidative Stress
* PPAR gamma
* RNA
* Vascular Diseases
* Vasodilation
|keywords=* NADPH oxidases
* acetylcholine
* carotid arteries
* nitric oxide
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002945
}}
{{medline-entry
|title=Upregulation of lactate-inducible snail protein suppresses oncogene-mediated senescence through p16  inactivation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29482580
|abstract=The preferential use of aerobic glycolysis by tumor cells lead to high accumulation of lactate in tumor microenvironment. Clinical evidence has linked elevated lactate concentration with cancer outcomes. However, the role and molecular mechanisms of lactate in cellular senescence and tumor progression remain elusive. The function of Snail in lactate-induced EMT in lung cancer cells was explored by wound healing assay and cell invasion assay. The qRT-PCR and dual luciferase reporter assay were performed to investigate how lactate regulates Snail expression. The level of TGF-β1 in culture supernatant of cells was measured by ELISA for its correlation with extracellular levels of lactate. Ras activity assay and SA-β-gal activity assay were established to determine the effect of lactate on oncogene-induced senescence in human lung epithelial cells. ChIP assays were conducted to determine the binding of snail to p16  promoter. Two TCGA data sets (TCGA-LUAD and TCGA-LUSC) were used to explore the correlations between [[SNAI1]] and [[[[CDKN2A]]]] expression. In this study, we showed the invasive and migratory potential of lung cancer cells was significantly enhanced by lactate and was directly linked to snail activity. We also demonstrated that extracellular acidification itself is a direct cause of the increased snail expression and physiologically coupled to [[LDHA]]-dependent conversion of pyruvate to lactate. Mechanistically, lactate exerts its central function in induction of snail and EMT by directly remodeling ECM and releasing activated TGF-β1. We also demonstrated that Snail help premalignant cells to escape the oncogene-induced senescence by directly targeting and inhibiting p16  expression. Our study extends the understanding of EMT in tumorigenesis by uncovering the role of snail in cellular senescence. This study also reveals lactate may be a potent tumor-promoting factor and provides the basis for the development of lactate-targeted therapy.
|mesh-terms=* Alveolar Epithelial Cells
* Animals
* Cell Line, Tumor
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Epithelial-Mesenchymal Transition
* Gene Expression
* Genes, Reporter
* Humans
* Hydrogen-Ion Concentration
* Lactic Acid
* Lung Neoplasms
* Models, Biological
* Neoplasms
* Oncogenes
* Rats
* Signal Transduction
* Smad Proteins
* Snail Family Transcription Factors
* Transforming Growth Factor beta1
* ras Proteins
|keywords=* Lactate
* Oncogene-induced senescence
* TGF-β1
* Tumor acidic microenvironment
* p16INK4a
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828408
}}
{{medline-entry
|title=Cellular aging dynamics after acute malaria infection: A 12-month longitudinal study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29143441
|abstract=Accelerated cellular aging and reduced lifespan have recently been shown in birds chronically infected with malaria parasites. Whether malaria infection also affects cellular aging in humans has not been reported. Here, we assessed the effect of a single acute Plasmodium falciparum malaria infection on cellular aging dynamics in travelers prospectively followed over one year in Sweden. DNA and RNA were extracted from venous blood collected at the time of admission and repeatedly up to one year. Telomere length was measured using real-time quantitative PCR, while telomerase activity and [[[[CDKN2A]]]] expression were measured by reverse transcriptase (RT)-qPCR. Our results show that acute malaria infection affects cellular aging as reflected by elevated levels of [[[[CDKN2A]]]] expression, lower telomerase activity, and substantial telomere shortening during the first three months postinfection. After that [[[[CDKN2A]]]] expression declined, telomerase activity increased and telomere length was gradually restored over one year, reflecting that cellular aging was reversed. These findings demonstrate that malaria infection affects cellular aging and the underlying cellular mechanism by which pathogens can affect host cellular aging and longevity need to be elucidated. Our results urge the need to investigate whether repeated malaria infections have more pronounced and long-lasting effects on cellular aging and lifespan (similarly to what was observed in birds) in populations living in malaria endemic areas.
|mesh-terms=* Adult
* Aged
* Cellular Senescence
* Female
* Humans
* Longevity
* Longitudinal Studies
* Malaria
* Male
* Middle Aged
* Telomerase
* Telomere
|keywords=* 
Plasmodium falciparum

* CDKN2A
* Malaria
* Telomerase
* Telomeres
* cellular aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771395
}}
{{medline-entry
|title=[[ARID1A]] suppresses malignant transformation of human pancreatic cells via mediating senescence-associated miR-503/[[[[CDKN2A]]]] regulatory axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28942143
|abstract=[[ARID1A]] as a subunit of SWI/SNF chromatin complexes is frequently mutated in human pancreatic cancer, however its exact role in pancreatic tumorigenesis remain unclear. In this study, we investigated the effects of [[ARID1A]] loss on human pancreatic epithelial cell lines HPNE, BxPC-3 with [[KRAS]] mutant ([[KRAS]] ) expression. We found that [[ARID1A]] knockdown promoted cell proliferation and colony formation in cooperation with active mutant [[KRAS]] . Function assay revealed that [[ARID1A]] knockdown accelerated cell cycle progression, and repressed [[KRAS]] -induced cell senescence. Transcriptome analysis revealed [[ARID1A]] knockdown led to miR-503 upregulation. [[[[CDKN2A]]]] was identified as a target of miR-503, which contributes to cell senescence. Thus, our data suggests that [[ARID1A]] deficiency promote [[KRAS]] -driven pancreatic tumorigenesis through miR-503/[[[[CDKN2A]]]]-mediated senescence.
|mesh-terms=* Carcinogenesis
* Cell Cycle
* Cell Line, Tumor
* Cell Proliferation
* Cell Transformation, Neoplastic
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p18
* DNA-Binding Proteins
* Gene Expression Profiling
* Gene Expression Regulation, Neoplastic
* Humans
* MicroRNAs
* Nuclear Proteins
* Pancreas
* Pancreatic Neoplasms
* Point Mutation
* Proto-Oncogene Proteins p21(ras)
* RNA Interference
* RNA, Small Interfering
* Transcription Factors
|keywords=* ARID1A
* Pancreatic cancer
* SWI/SNF
* Senescence
* miR-503
* microRNA
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2017.09.099
}}
{{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=Identification of the activating cytotoxicity receptor NKG2D as a senescence marker in zero-hour kidney biopsies is indicative for clinical outcome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28233611
|abstract=The definition of biological donor organ age rather than chronological age seems obvious for the establishment of a valid pre-transplant risk assessment. Therefore, we studied gene expression for candidate markers in 60 zero-hour kidney biopsies. Compared with 29 younger donors under age 55, 31 elderly donors age 55 and older had significant mRNA expression for immunoproteasome subunits (PSMB8, [[PSMB9]] and [[PSMB10]]), HLA-DRB, and transcripts of the activating cytotoxicity receptor NKG2D. Gene expression was validated in an independent donor cohort consisting of 37 kidneys from donors 30 years and under (Group I), 75 kidneys from donors age 31-54 years (Group II) and 75 kidneys from donors age 55 and older (Group III). Significant gene induction was confirmed in kidneys from Group III for [[PSMB9]] and [[PSMB10]]. Strikingly, transcripts of NKG2D had the significantly highest gene induction in Group III versus Group II and Group I. Similar results were obtained for [[[[CDKN2A]]]], but not for telomere length. Both NKG2D and [[[[CDKN2A]]]] mRNA expression were significantly correlated with creatinine levels at 24 months after transplantation. Univariate regression analysis showed significant predictive power regarding graft function at 6 and 12 months for NKG2D and [[[[CDKN2A]]]]. However, only NKG2D remained significantly predictive in the multivariate model at 12 months. Thus, our results reveal novel candidate markers in aged renal allografts, which could be helpful in the assessment of organ quality.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Austria
* Biopsy
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p18
* Cysteine Endopeptidases
* Delayed Graft Function
* Donor Selection
* Female
* Gene Expression Regulation
* Genetic Markers
* Germany
* Graft Rejection
* Graft Survival
* HLA-DR beta-Chains
* Humans
* Kidney
* Kidney Transplantation
* Logistic Models
* Male
* Middle Aged
* Multivariate Analysis
* NK Cell Lectin-Like Receptor Subfamily K
* Predictive Value of Tests
* Proteasome Endopeptidase Complex
* RNA, Messenger
* Risk Factors
* Telomere Homeostasis
* Time Factors
* Tissue Donors
* Treatment Outcome
* Young Adult
|keywords=* NKG2D
* kidney
* senescence
* zero-hour biopsy
|full-text-url=https://sci-hub.do/10.1016/j.kint.2016.12.018
}}
{{medline-entry
|title=ETS Proto-oncogene 1 Transcriptionally Up-regulates the Cholangiocyte Senescence-associated Protein Cyclin-dependent Kinase Inhibitor 2A.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28184004
|abstract=Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory cholangiopathy (disease of the bile ducts) of unknown pathogenesis. We reported that cholangiocyte senescence features prominently in PSC and that neuroblastoma RAS viral oncogene homolog ([[NRAS]]) is activated in PSC cholangiocytes. Additionally, persistent microbial insult ([i]e.g.[/i] LPSs) induces cyclin-dependent kinase inhibitor 2A ([[[[CDKN2A]]]]/p16 ) expression and senescence in cultured cholangiocytes in an [[NRAS]]-dependent manner. However, the molecular mechanisms involved in LPS-induced cholangiocyte senescence and [[NRAS]]-dependent regulation of [[[[CDKN2A]]]] remain unclear. Using our [i]in vitro[/i] senescence model, we found that LPS-induced [i][[[[CDKN2A]]]][/i] expression coincided with a 4.5-fold increase in [i][[ETS1]][/i] ([i]ETS proto-oncogene 1[/i]) mRNA, suggesting that [[ETS1]] is involved in regulating [i][[[[CDKN2A]]]][/i] This idea was confirmed by RNAi-mediated suppression or genetic deletion of [[ETS1]], which blocked [[[[CDKN2A]]]] expression and reduced cholangiocyte senescence. Furthermore, site-directed mutagenesis of a predicted ETS-binding site within the [i][[[[CDKN2A]]]][/i] promoter abolished luciferase reporter activity. Pharmacological inhibition of RAS/MAPK reduced [[ETS1]] and [[[[CDKN2A]]]] protein expression and [i][[[[CDKN2A]]]][/i] promoter-driven luciferase activity by ∼50%. In contrast, constitutively active [[NRAS]] expression induced [[ETS1]] and [[[[CDKN2A]]]] protein expression, whereas [[ETS1]] RNAi blocked this increase. Chromatin immunoprecipitation-PCR detected increased [[ETS1]] and histone 3 lysine 4 trimethylation (H3K4Me3) at the [i][[[[CDKN2A]]]][/i] promoter following LPS-induced senescence. Additionally, phospho-[[ETS1]] expression was increased in cholangiocytes of human PSC livers and in the [i]Abcb4[/i] ([i]Mdr2[/i])  mouse model of PSC. These data pinpoint [[ETS1]] and H3K4Me3 as key transcriptional regulators in [[NRAS]]-induced expression of [i][[[[CDKN2A]]]][/i], and this regulatory axis may therefore represent a potential therapeutic target for PSC treatment.
|mesh-terms=* Animals
* Cell Line
* Cellular Senescence
* Cholangitis, Sclerosing
* Cyclin-Dependent Kinase Inhibitor p16
* Humans
* Lipopolysaccharides
* Liver
* Mice
* Proto-Oncogene Protein c-ets-1
* RNA, Messenger
* Transcriptional Activation
* Up-Regulation
|keywords=* CDKN2A
* Cholangiocytes
* ETS1
* cell signaling
* epigenetics
* epithelial cell
* senescence
* transcription
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377799
}}
{{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=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=Targeting genes in insulin-associated signalling pathway, DNA damage, cell proliferation and cell differentiation pathways by tocotrienol-rich fraction in preventing cellular senescence of human diploid fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26794818
|abstract=Tocotrienols have been known for their antioxidant properties besides their roles in cellular signalling, gene expression, immune response and apoptosis. This study aimed to determine the molecular mechanism of tocotrienol-rich fraction (TRF) in preventing cellular senescence of human diploid fibroblasts (HDFs) by targeting the genes in senescence-associated signalling pathways. Real time quantitative PCR (qRT-PCR) was utilized to evaluate the expression of genes involved in these pathways. Our findings showed that [[SOD1]] and [[CCS]]-1 were significantly down-regulated in pre-senescent cells while [[CCS]]-1 and [[PRDX6]] were up-regulated in senescent cells (p<0.05). Treatment with TRF significantly down-regulated [[SOD1]] in pre-senescent and senescent HDFs, up-regulated [[SOD2]] in senescent cells, [[CAT]] in young HDFs, [[GPX1]] in young and pre-senescent HDFs, and [[CCS]]-1 in young, pre-senescent and senescent HDFs (p<0.05). TRF treatment also caused up-regulation of FOXO3A in all age groups of cells (p<0.05). The expression of [[TP53]], [[PAK2]] and [[[[CDKN2A]]]] was significantly increased in senescent HDFs and treatment with TRF significantly down-regulated [[TP53]] in senescent cells (p<0.05). [[MAPK14]] was significantly up-regulated (p<0.05) in senescent HDFs while no changes was observed on the expression of [[JUN]]. TRF treatment, however, down-regulated [[MAPK14]] in young and senescent cells and up-regulated [[JUN]] in young and pre-senescent HDFs (p<0.05). TRF modulated the expression of genes involved in senescence-associated signalling pathways during replicative senescence of HDFs.
|mesh-terms=* Antioxidants
* Cell Differentiation
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* DNA Damage
* Diploidy
* Down-Regulation
* Fibroblasts
* Genetic Markers
* Humans
* Insulins
* Real-Time Polymerase Chain Reaction
* Signal Transduction
* Tocotrienols
* Up-Regulation
|keywords=* Cellular senescence
* Genes expression
* Senescence-associated signalling pathways
* Tocotrienol-rich fraction
|full-text-url=https://sci-hub.do/10.7417/T.2015.1902
}}
{{medline-entry
|title=Alterations of telomere length and DNA methylation in hairdressers: A cross-sectional study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26637967
|abstract=Working as hairdressers has been associated with increased risk for cancer, particularly bladder cancer. To evaluate if current hairdressers have elevated risks of adverse health effects, we measured several biomarkers related to cancer-related DNA alterations. We enrolled 295 hairdressers and 92 non-hairdressers (all female non-smokers) from Stockholm and southern Sweden. Questionnaire data were collected for each participant, including work tasks for the hairdressers. We measured telomere length in peripheral blood leucocytes using quantitative PCR and DNA methylation status of genes relevant for bladder cancer using methylation sensitive high resolution melting analysis. The hairdressers had shorter telomeres (β = -0.069, P = 0.019) compared with non-hairdressers. Shorter telomeres were found in hairdressers up to 32 years old performing hair waving more than once per week as compared with hairdressers in the same age group performing hair waving less often (β = -0.12, P = 0.037). Hair waving was associated with less frequent [[[[CDKN2A]]]] methylation (odds ratio, OR = 0.19, P = 0.033). Shorter telomeres in hairdressers may indicate a genotoxic effect. Performing hair waving was associated with short telomere length, although the effect was only observed in young hairdressers. No clear patterns were discerned with regard to DNA methylation of bladder cancer-related genes. The observed changes of methylation were not all in the expected direction and warrant further investigation.
|mesh-terms=* Adult
* Aging
* Case-Control Studies
* Cross-Sectional Studies
* Cyclin-Dependent Kinase Inhibitor p16
* DNA Methylation
* DNA Modification Methylases
* DNA Repair Enzymes
* Female
* Glutathione S-Transferase pi
* Humans
* Middle Aged
* Nuclear Proteins
* Occupational Diseases
* Occupational Exposure
* Sweden
* Telomere
* Time Factors
* Tumor Suppressor Proteins
* Twist-Related Protein 1
* Young Adult
|keywords=* cancer risk
* epigenetic
* genotoxicity
* occupational exposure
* toluidine
|full-text-url=https://sci-hub.do/10.1002/em.21991
}}
{{medline-entry
|title=Genetics of melanoma progression: the rise and fall of cell senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26386262
|abstract=There are many links between cell senescence and the genetics of melanoma, meaning both familial susceptibility and somatic-genetic changes in sporadic melanoma. For example, [[[[CDKN2A]]]], the best-known melanoma susceptibility gene, encodes two effectors of cell senescence, while other familial melanoma genes are related to telomeres and their maintenance. This article aimed to analyze our current knowledge of the genetic or epigenetic driver changes necessary to generate a cutaneous metastatic melanoma, the commonest order in which these occur, and the relation of these changes to the biology and pathology of melanoma progression. Emphasis is laid on the role of cell senescence and the escape from senescence leading to cellular immortality, the ability to divide indefinitely.
|mesh-terms=* Animals
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Genetic Predisposition to Disease
* Humans
* Melanoma
* Neoplasm Metastasis
* Neoplasm Proteins
* Skin Neoplasms
* Telomere
* Telomere Homeostasis
|keywords=* TERT
* immortalization
* melanoma
* metamortal
* nevus
* p16
* senescence
|full-text-url=https://sci-hub.do/10.1111/pcmr.12422
}}
{{medline-entry
|title=Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26391655
|abstract=Autophagy is triggered in vascular smooth muscle cells (VSMCs) of diseased arterial vessels. However, the role of VSMC autophagy in cardiovascular disease is poorly understood. Therefore, we investigated the effect of defective autophagy on VSMC survival and phenotype and its significance in the development of postinjury neointima formation and atherosclerosis. Tissue-specific deletion of the essential autophagy gene Atg7 in murine VSMCs (atg7  VSMCs) caused accumulation of [[SQSTM1]]/p62 and accelerated the development of stress-induced premature senescence as shown by cellular and nuclear hypertrophy, [[[[CDKN2A]]]]-RB-mediated G  proliferative arrest and senescence-associated [[GLB1]] activity. Transfection of [[SQSTM1]]-encoding plasmid DNA in Atg7  VSMCs induced similar features, suggesting that accumulation of [[SQSTM1]] promotes VSMC senescence. Interestingly, atg7  VSMCs were resistant to oxidative stress-induced cell death as compared to controls. This effect was attributed to nuclear translocation of the transcription factor [[NFE2L2]] resulting in upregulation of several antioxidative enzymes. In vivo, defective VSMC autophagy led to upregulation of [[MMP9]], TGFB and [[CXCL12]] and promoted postinjury neointima formation and diet-induced atherogenesis. Lesions of VSMC-specific atg7 knockout mice were characterized by increased total collagen deposition, nuclear hypertrophy, [[[[CDKN2A]]]] upregulation, RB hypophosphorylation, and [[GLB1]] activity, all features typical of cellular senescence. To conclude, autophagy is crucial for VSMC function, phenotype, and survival. Defective autophagy in VSMCs accelerates senescence and promotes ligation-induced neointima formation and diet-induced atherogenesis, implying that autophagy inhibition as therapeutic strategy in the treatment of neointimal stenosis and atherosclerosis would be unfavorable. Conversely, stimulation of autophagy could be a valuable new strategy in the treatment of arterial disease.

|keywords=* atherosclerosis
* autophagy
* neointima formation
* senescence
* sequestosome 1/p62
* vascular smooth muscle cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824610
}}
{{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=Y-27632, a ROCK inhibitor, delays senescence of putative murine salivary gland stem cells in culture.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25804560
|abstract=A loss of functional salivary glands often occurs after radiotherapy for head and neck tumour, and causes many problems in oral health. Recently, the use of salispheres, which consist of salivary gland stem cells (SGSCs), has been suggested as therapy for these problems. However, an insufficient number of cells can be obtained and cultured for cell transplantation. In the present study, salispheres were propagated and passaged by suspension culture to acquire a sufficient number of SGSCs for cell therapy. The relationship between sphere formation and the degree of cellular senescence was investigated by analysing senescence-associated β-galactosidase activity and the expression of senescence-related markers such as [[[[CDKN2A]]]] (p16) and p21. Because the sphere formation potential of SGSCs was decreased and the senescence of the cells was increased after passaging subculture, Y-27632, a Rho-associated kinase inhibitor, was used to treat the passaging subculture to aid the proliferation of the cells in culture. The number of spheres was higher in the Y-27632 treatment group than in the control group, and the expression of c-Kit, a proliferation marker, was also increased. In addition, the expression of p16 and p21 proteins tended to be lower in the Y-27632 group. Y-27632 suppresses the expression of senescence-related proteins and enhances cellular proliferation. This study points to the possibility of scaling-up the therapeutic use of SGSCs, which requires a large amount of cells.
|mesh-terms=* Amides
* Animals
* Cell Culture Techniques
* Cellular Senescence
* Female
* Mice
* Mice, Inbred C57BL
* Pyridines
* Salivary Glands
* Stem Cells
|keywords=* Rho-associated kinase inhibitor
* Salisphere
* Salivary gland stem cell
* Senescence
* Small molecule
* Suspension culture
|full-text-url=https://sci-hub.do/10.1016/j.archoralbio.2015.03.003
}}
{{medline-entry
|title=Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24876127
|abstract=Cellular senescence is a crucial tumor suppressor mechanism. We discovered a CAPERα/[[TBX3]] repressor complex required to prevent senescence in primary cells and mouse embryos. Critical, previously unknown roles for CAPERα in controlling cell proliferation are manifest in an obligatory interaction with [[TBX3]] to regulate chromatin structure and repress transcription of [[[[CDKN2A]]]]-p16INK and the RB pathway. The IncRNA UCA1 is a direct target of CAPERα/[[TBX3]] repression whose overexpression is sufficient to induce senescence. In proliferating cells, we found that hnRNPA1 binds and destabilizes [[[[CDKN2A]]]]-p16INK mRNA whereas during senescence, UCA1 sequesters hnRNPA1 and thus stabilizes [[[[CDKN2A]]]]-p16INK. Thus CAPERα/[[TBX3]] and UCA1 constitute a coordinated, reinforcing mechanism to regulate both [[[[CDKN2A]]]]-p16INK transcription and mRNA stability. Dissociation of the CAPERα/[[TBX3]] co-repressor during oncogenic stress activates UCA1, revealing a novel mechanism for oncogene-induced senescence. Our elucidation of CAPERα and UCA1 functions in vivo provides new insights into senescence induction, and the oncogenic and developmental properties of [[TBX3]]. 
|mesh-terms=* Animals
* Cell Proliferation
* Cellular Senescence
* Chromatin
* Cyclin-Dependent Kinase Inhibitor p16
* Fibroblasts
* Heterogeneous Nuclear Ribonucleoprotein A1
* Heterogeneous-Nuclear Ribonucleoprotein Group A-B
* Humans
* Mass Spectrometry
* Mice
* Nuclear Proteins
* Oncogenes
* Promoter Regions, Genetic
* Protein Structure, Tertiary
* RNA, Long Noncoding
* RNA, Messenger
* RNA-Binding Proteins
* T-Box Domain Proteins
|keywords=* cell biology
* development
* developmental biology
* mouse
* oncogenesis
* p16
* senescence
* stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071561
}}
{{medline-entry
|title=Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer's disease animal model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24194717
|abstract=Harboring the behavioral and histopathological signatures of Alzheimer's disease (AD), senescence accelerated mouse-prone 8 (SAMP8) mice are currently considered a robust model for studying AD. However, the underlying mechanisms, prioritized pathways and genes in SAMP8 mice linked to AD remain unclear. In this study, we provide a biological interpretation of the molecular underpinnings of SAMP8 mice. Our results were derived from differentially expressed genes in the hippocampus and cerebral cortex of SAMP8 mice compared to age-matched SAMR1 mice at 2, 6, and 12 months of age using cDNA microarray analysis. On the basis of PPI, MetaCore and the co-expression network, we constructed a distinct genetic sub-network in the brains of SAMP8 mice. Next, we determined that the regulation of synaptic transmission and apoptosis were disrupted in the brains of SAMP8 mice. We found abnormal gene expression of [[RAF1]], [[MAPT]], [[PTGS2]], [[[[CDKN2A]]]], [[CAMK2A]], [[NTRK2]], [[AGER]], ADRBK1, [[MCM3AP]], and [[STUB1]], which may have initiated the dysfunction of biological processes in the brains of SAMP8 mice. Specifically, we found microRNAs, including miR-20a, miR-17, miR-34a, miR-155, miR-18a, miR-22, miR-26a, miR-101, miR-106b, and miR-125b, that might regulate the expression of nodes in the sub-network. Taken together, these results provide new insights into the biological and genetic mechanisms of SAMP8 mice and add an important dimension to our understanding of the neuro-pathogenesis in SAMP8 mice from a systems perspective. 

|keywords=* Alzheimer's disease
* apoptosis
* cerebral cortex
* differential expressed genes
* hippocampus
* molecular network
* senescence accelerated mouse prone 8
* synaptic transmission
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810591
}}
{{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=Ocular parameters of biological ageing in HIV-infected individuals in South Africa: relationship with chronological age and systemic biomarkers of ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23994067
|abstract=HIV-infected individuals have an increased risk of age-related morbidity despite antiretroviral treatment (ART). Several anatomic and functional ophthalmological parameters are associated with increasing chronological age. These may, therefore, potentially serve as biomarkers of ageing. We investigated associations between ocular parameters (lens density, retinal vessel calibre, corneal endothelium and retinal nerve fibre layer thickness) and two 'cellular' biomarkers of ageing (leukocyte telomere length and [[[[CDKN2A]]]] expression) and with frailty in a cross-sectional study of 216 HIV-infected individuals. All ocular parameters, telomere length and frailty were associated with chronological age, whereas [[[[CDKN2A]]]] expression was not. Retinal venular calibre and lens density were associated with shorter telomere length (p-trend=0.04, and 0.08, respectively), whereas [[[[CDKN2A]]]] expression and frailty status were not associated with ocular parameters. Longitudinal studies are warranted to assess the integration of retinal vascular calibre and lens density with systemic markers to develop an overall index of biological ageing in HIV infection. 
|mesh-terms=* Adult
* Aging
* Anthropometry
* Anti-Retroviral Agents
* Biomarkers
* Blood Pressure
* Cornea
* Cross-Sectional Studies
* Cyclin-Dependent Kinase Inhibitor p16
* Female
* HIV Infections
* Humans
* Lens, Crystalline
* Male
* Middle Aged
* Retina
* Retinal Vessels
* South Africa
* Telomere
* Vision, Ocular
|keywords=* CDKN2A
* HIV
* Lens density
* Retinal vessel calibre
* Telomeres
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818088
}}
{{medline-entry
|title=CDK4/6-inhibiting drug substitutes for p21 and p16 in senescence: duration of cell cycle arrest and [[MTOR]] activity determine geroconversion.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23974099
|abstract=CDKN1A (p21) and [[[[CDKN2A]]]] (p16) inhibit CDK4/6, initiating senescence. According to our view on senescence, the role of p21 and p16 is to cause cell cycle arrest, whereas [[MTOR]] (mechanistic target of rapamycin) drives geroconversion to senescence. Recently we demonstrated that one of the markers of p21- and p16-initiated senescence is MEK-dependent hyper-elevation of cyclin D1. We noticed that a synthetic inhibitor of CDK 4/6 (PD0332991) also induced cyclin D1-positive senescence. We demonstrated that PD0332991 and p21 caused almost identical senescence phenotypes. p21, p16, and PD0332991 do not inhibit [[MTOR]], and rapamycin decelerates geroconversion caused by all 3 molecules. Like p21, PD0332991 initiated senescence at any concentration that inhibited cell proliferation. This confirms the notion that a mere arrest in the presence of active [[MTOR]] may lead to senescence. 
|mesh-terms=* Butadienes
* Cell Cycle Checkpoints
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Cyclin D1
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase 6
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* Humans
* Nitriles
* Piperazines
* Pyridines
* Sirolimus
* TOR Serine-Threonine Kinases
|keywords=* CDKN1A
* CDKN2A
* aging
* cancer
* rapalogs
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875680
}}
{{medline-entry
|title=Accelerated biological ageing in HIV-infected individuals in South Africa: a case-control study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23751258
|abstract=Little is known about the impact of HIV infection on biological ageing in sub-Saharan Africa. The study aimed to assess biological ageing in South African HIV-infected adults and HIV-seronegative individuals using two validated biomarkers, telomere length and [[[[CDKN2A]]]] expression (a mediator of cellular senescence). A case-control study. Two hundred and thirty-six HIV-infected adults aged at least 30 years and 250 age and sex frequency matched HIV-seronegative individuals were recruited from clinics in township communities in Cape Town. Biological ageing was evaluated by measurement of telomere length and [[[[CDKN2A]]]] expression in peripheral blood leukocytes. The median ages of the HIV-infected and HIV-seronegative participants were 39 and 40 years, respectively. Among HIV-infected participants, 87.1% were receiving antiretroviral therapy (ART), their median CD4⁺ cell count was 468 cells/μl and 84.3% had undetectable viral load. Both biomarkers were validated against chronological age in HIV-seronegative individuals. Telomere length was significantly shorter in HIV-infected individuals than in HIV-seronegative individuals (mean relative T/S ratio ±SE:0.91 ± 0.007 vs. 1.07 ± 0.008, P < 0.0001). CD2NKA expression was higher in HIV-infected participants than in HIV-seronegative individuals (mean expression: 0.45 ± 0.02 vs. 0.36 ± 0.03, P = 0.003). Socioeconomic factors were not associated with biological ageing in HIV-infected participants. However, in participants on ART with undetectable viral load, biomarker levels indicated greater biological ageing in those with lower current CD4⁺ cell counts. Telomere length and [[[[CDKN2A]]]] expression were both consistent with increased biological ageing in HIV-infected individuals. Prospective studies of the impact of HIV on biological ageing in sub-Saharan Africa are warranted.
|mesh-terms=* Adult
* Aging
* Anti-Retroviral Agents
* CD4 Lymphocyte Count
* Case-Control Studies
* Cyclin-Dependent Kinase Inhibitor p16
* Female
* HIV Infections
* Humans
* Leukocytes
* Male
* Middle Aged
* South Africa
* Telomere
* Viral Load

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805356
}}
{{medline-entry
|title=Assessment of candidate ocular biomarkers of ageing in a South African adult population: relationship with chronological age and systemic biomarkers.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23701820
|abstract=Certain anatomic and functional parameters of the eye change with increasing chronological age. They may, therefore, serve as potential biomarkers of ageing. We investigated associations between four such ocular parameters (lens density, retinal vessel calibre, corneal endothelial cells and retinal nerve fibre layer thickness) and two 'cellular' biomarkers of ageing (leukocyte telomere length and [[[[CDKN2A]]]] expression), with frailty (a clinical correlate of biological ageing) in a population of South African adults. All ocular parameters revealed an association with either telomere length or [[[[CDKN2A]]]] expression. However, lens density was most strongly correlated with age, increased [[[[CDKN2A]]]] expression, and with frailty (p=0.05 and 0.03, respectively). Narrow retinal arteriolar diameter, associated with increased chronological age, was also associated with increased CDK2NA expression (0.42 vs. 0.31, p=0.02) but not with frailty. Ocular parameters may aid in determining biological age, warranting investigation in longitudinal studies. 
|mesh-terms=* Adult
* Aging
* Biomarkers
* Cyclin-Dependent Kinase Inhibitor p16
* Female
* Gene Expression Regulation
* Humans
* Leukocytes
* Male
* Middle Aged
* Retina
* Retinal Vessels
* South Africa
* Telomere

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710972
}}
{{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=Differential expression of senescence and cell death factors in non-small cell lung and colorectal tumors showing telomere attrition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22433385
|abstract=The main aim of this work is to investigate the expression of factors related to senescence and cell death pathways in non-small cell lung cancers (NSCLCs) and colorectal cancers (CRCs) in relation to telomere status. We analyzed 158 tissue samples, 36 NSCLCs, 43 CRCs, and their corresponding control tissues obtained from patients submitted to surgery. Telomere function was evaluated by determining telomerase activity and telomere length. Expression of factors related to senescence, cell death pathways, transformation and tumorigenesis was investigated using arrays. Results were validated by real-time quantitative PCR. Considering tumors with telomere shortening, expression for [[BNIP3]], [[DAPK1]], [[NDRG1]], [[EGFR]], and [[[[CDKN2A]]]] was significantly higher in NSCLC than in CRC, whereas [[TP53]] was overexpressed in CRC with respect to NSCLC. Moreover, compared to nontumor samples, [[DAPK1]], [[GADD45A]], [[SHC1]], and [[TP53]] were downregulated in the group of NSCLCs with telomere shortening, and no significant differences were found in CRC. In NSCLC, the failure of pathways which involve factors such as [[DAPK1]], [[GADD45A]], [[SHC1]], and [[TP53]], in response to short telomeres, could promote tumor progression. In CRC, the viability of these pathways in response to short telomeres could contribute to limiting tumorigenesis.
|mesh-terms=* Adenocarcinoma
* Aged
* Aging
* Biomarkers, Tumor
* Carcinoma, Large Cell
* Carcinoma, Non-Small-Cell Lung
* Carcinoma, Squamous Cell
* Cell Death
* Colon
* Colorectal Neoplasms
* Female
* Gene Expression Profiling
* Humans
* Lung
* Lung Neoplasms
* Male
* Oligonucleotide Array Sequence Analysis
* Prognosis
* Rectum
* Telomerase
* Telomere
* Telomere Shortening

|full-text-url=https://sci-hub.do/10.1159/000335678
}}
{{medline-entry
|title=Improving precision in investigating aging: why telomeres can cause problems.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20538902
|abstract=A host of recent publications has highlighted a growing number of discrepancies between small-scale laboratory-based studies and larger clinical and epidemiological studies, using telomere length as a bio-aging marker for physical, sociological, and psychological parameters in their respective cohorts. These discrepancies may be rooted in differing telomere length measurement methods and their application. This leads to the question of just how robust telomere length is as a biomarker of aging and whether measurement of [[[[CDKN2A]]]] levels offers a better alternative. The latter has already provided reproducible data from a small number of clinical studies and in one proven better than telomere length determination in predicting organ function. It seems prudent to address the use of these markers, alone or in combination, in multicentre double-blinded studies, using standardized methodologies and reagents, in order to identify the most appropriate marker and method for investigating bio-aging.
|mesh-terms=* Adult
* Aged
* Aging
* Biomarkers
* Blotting, Southern
* Cyclin-Dependent Kinase Inhibitor p16
* Humans
* Middle Aged
* Telomere

|full-text-url=https://sci-hub.do/10.1093/gerona/glq095
}}
{{medline-entry
|title=Genetic variation in healthy oldest-old.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19680556
|abstract=Individuals who live to 85 and beyond without developing major age-related diseases may achieve this, in part, by lacking disease susceptibility factors, or by possessing resistance factors that enhance their ability to avoid disease and prolong lifespan. Healthy aging is a complex phenotype likely to be affected by both genetic and environmental factors. We sequenced 24 candidate healthy aging genes in DNA samples from 47 healthy individuals aged eighty-five years or older (the 'oldest-old'), to characterize genetic variation that is present in this exceptional group. These healthy seniors were never diagnosed with cancer, cardiovascular disease, pulmonary disease, diabetes, or Alzheimer disease. We re-sequenced all exons, intron-exon boundaries and selected conserved non-coding sequences of candidate genes involved in aging-related processes, including dietary restriction (PPARG, [[PPARGC1A]], [[SIRT1]], [[SIRT3]], [[UCP2]], UCP3), metabolism (IGF1R, [[APOB]], SCD), autophagy (BECN1, FRAP1), stem cell activation (NOTCH1, DLL1), tumor suppression (TP53, [[[[CDKN2A]]]], ING1), DNA methylation (TRDMT1, [[DNMT3A]], DNMT3B) Progeria syndromes (LMNA, [[ZMPSTE24]], KL) and stress response (CRYAB, HSPB2). We detected 935 variants, including 848 single nucleotide polymorphisms (SNPs) and 87 insertion or deletions; 41% (385) were not recorded in dbSNP. This study is the first to present a comprehensive analysis of genetic variation in aging-related candidate genes in healthy oldest-old. These variants and especially our novel polymorphisms are valuable resources to test for genetic association in models of disease susceptibility or resistance. In addition, we propose an innovative tagSNP selection strategy that combines variants identified through gene re-sequencing- and HapMap-derived SNPs.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Genetic Variation
* Humans
* Polymorphism, Single Nucleotide

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722017
}}
{{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
}}