Редактирование: E2F1

Transcription factor E2F1 (E2F-1) (PBR3) (Retinoblastoma-associated protein 1) (RBAP-1) (Retinoblastoma-binding protein 3) (RBBP-3) (pRB-binding protein E2F-1) [RBBP3]

==Publications==

{{medline-entry
|title=Regulation of [[E2F1]] activity via PKA-mediated phosphorylations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33110360
|abstract=[[E2F1]] becomes activated during the G1 phase of the cell cycle, and posttranslational modifications modulate its activity. Activation of G-protein coupled receptors (GPCR) by many ligands induces the activation of adenylate cyclases and the production of cAMP, which activates the PKA enzyme. Activated PKA elicits its biological effect by phosphorylating the target proteins containing serine or threonine amino acids in the RxxS/T motif. Since PKA activation negatively regulates cell proliferation, we thought that activated PKA would negatively affect the activity of [[E2F1]]. In line with this, when we analyzed the amino acid sequence of [[E2F1]], we found 3 hypothetical consensus PKA phosphorylation sites located at 127-130, 232-235, and 361-364 positions and RYET, RLLS, and RMGS sequences. After showing the binding and phosphorylation of [[E2F1]] by PKA, we converted the codons of Threonine-130, Serine-235, and Serine-364 to Alanine and Glutamic acid codons on the eukaryotic [[E2F1]] expression vector we had previously created. We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of [[E2F1]] by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence.

|keywords=* E2F1
* PKA
* cell cycle
* forskolin
* proliferation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585165
}}
{{medline-entry
|title=p53 inhibits the osteogenic differentiation but does not induce senescence in human dental follicle cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32473528
|abstract=Replicative senescence causes a reduced osteogenic differentiation potential of senescent dental follicle cells (DFCs). The transcription factor p53 is often involved in the induction of cellular senescence, but little is known about its role in DFCs. This study examined for the first time the role of p53 compared to its pro-proliferative antagonist E2F-1 in terms of osteogenic differentiation potential and induction of senescence. Protein expression of E2F-1 decreased during cell aging, while p53 was expressed constitutively. Gene silencing of [[E2F1]] (E2F-1) inhibited the proliferation rate of DFCs and increased the induction of cellular senescence. The induction of cellular senescence is regulated independently of the gene expression of [[TP53]] (p53), since its gene expression depends on the expression of [[E2F1]]. Moreover, gene silencing of [[TP53]] induced [[E2F1]] gene expression and increased cell proliferation, but did not affect the rate of induction of cellular senescence. [[TP53]] knockdown further induced the alkaline phosphatase and mineralization in DFCs. However, the simultaneous silencing of [[TP53]] and [[E2F1]] did not inhibit the inductive effect of [[TP53]] knockdown on osteogenic differentiation, indicating that this effect is independent of E2F-1. In summary, our results suggest that p53 inhibits osteogenic differentiation and cell proliferation in senescent DFCs, but is not significantly involved in senescence induction.

|keywords=* Cellular senescence
* Dental follicle cells
* E2F-1
* Osteogenic differentiation
* p53
|full-text-url=https://sci-hub.do/10.1016/j.diff.2020.05.003
}}
{{medline-entry
|title=Astragaloside IV ameliorates radiation-induced senescence via antioxidative mechanism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32412100
|abstract=Ageing is a universal and gradual process of organ deterioration. Radiation induces oxidative stress in cells, which leads to genetic damage and affects cell growth, differentiation and senescence. Astragaloside (AS)-IV has antioxidative, anti-apoptotic and anti-inflammatory properties. To study the protective mechanism of AS-IV on radiation-induced brain cell senescence, we constructed a radiation-induced brain cell ageing model, using biochemical indicators, senescence-associated galactosidase (SA-β-gal) senescence staining, flow cytometry and Western blotting to analyse the AS-IV resistance mechanism to radiation-induced brain cell senescence. Radiation reduced superoxide dismutase (SOD) activity and expressions of cyclin-dependent kinase (CDK2), [[CDK4]], cyclin E and transcription factor [[E2F1]] proteins, and increased expressions of p21, p16, cyclin D and retinoblastoma (RB) proteins, malondialdehyde (MDA) activity, SA-β-gal-positive cells and cells stagnating in G1 phase. After treatment with AS-IV, the level of oxidative stress in cells significantly decreased and expression of proteins related to the cell cycle and ageing significantly changed. In addition, SA-β-gal-positive cells and cells arrested in G1 phase were significantly reduced. These data suggest that AS-IV can antagonize radiation-induced brain cells senescence; and its mechanism may be related to p53-p21 and p16-RB signalling pathways of ageing regulation.

|keywords=* cell signal pathway
* nerve cells
* radiation
* senescence
|full-text-url=https://sci-hub.do/10.1111/jphp.13284
}}
{{medline-entry
|title=[[E2F1]] mediates the downregulation of [[POLD1]] in replicative senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30895337
|abstract=[[POLD1]], the catalytic subunit of DNA Pol δ, plays an important role in DNA synthesis and DNA damage repair, and [[POLD1]] is downregulated in replicative senescence and mediates cell aging. However, the mechanisms of age-related downregulation of [[POLD1]] expression have not been elucidated. In this study, four potential CpG islands in the [[POLD1]] promoter were found, and the methylation levels of the [[POLD1]] promoter were increased in aging 2BS cells, WI-38 cells and peripheral blood lymphocytes, especially at a single site, CpG 36, in CpG island 3. Then, the transcription factor [[E2F1]] was observed to bind to these sites. The binding affinity of [[E2F1]] for the [[POLD1]] promoter was found to show age-related attenuation and was confirmed to be positively regulated by the [[E2F1]] level and negatively regulated by [[POLD1]] promoter methylation. Moreover, cell senescence characteristics were observed in the cells transfected with shRNA-[[E2F1]] and could contribute to the downregulation of [[POLD1]] induced by the [[E2F1]] decline. Collectively, these results indicated that the attenuation of the binding affinity of [[E2F1]] for the [[POLD1]] promoter, mediated by an age-related decline in [[E2F1]] and increased methylation of CpG island 3, downregulates [[POLD1]] expression in aging.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Cells, Cultured
* Cellular Senescence
* CpG Islands
* DNA Methylation
* DNA Polymerase III
* DNA Repair
* DNA Replication
* Down-Regulation
* E2F1 Transcription Factor
* Female
* Gene Expression Regulation
* Healthy Volunteers
* Humans
* Male
* Middle Aged
* Promoter Regions, Genetic
* Young Adult
|keywords=* DNA methylation
* E2F1
* POLD1
* Replicative senescence
* Transcription factor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588650
}}
{{medline-entry
|title=Low dose Emodin induces tumor senescence for boosting breast cancer chemotherapy via silencing [[NRARP]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30274778
|abstract=The resistance to 5-FU often limits its clinical effectiveness on breast cancer treatment. Combination therapy thus is employed to overcome this treatment resistance. We here report a potent antitumor effect of Emodin at low dose on chemotherapy sensitivity of MCF-7 breast cancer cells. Cell viability, apoptosis, glutathiones (GSH) concentration and Reactive oxygen species (ROS) activity following Emodin and 5-FU treatment was assessed. Cellular senescence following combined treatment and silence of [[NRARP]] was examined by senescence-associated β-galactosidase analysis. Western blot analysis was used to determine changes in the expression of p21, p16, p27, [[E2F1]] and [[NRARP]]. Low dose Emodin potentiates 5-FU-induced apoptosis of breast cancer cells, in association with inhibition of [[NRARP]], resulting in cellular senescence. RNA interference of [[NRARP]] induced cellular senescence in MCF-7 breast cancer cells. Furthermore, the cellular senescence induced by Emodin and 5-FU treatment could be reverted by pcDNA-[[NRARP]]. These findings provide preclinical evidence for repurposing use of Emodin in combination with chemotherapeutic agents to treat breast cancer as an alternative salvage regimen.
|mesh-terms=* Antimetabolites, Antineoplastic
* Apoptosis
* Breast Neoplasms
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Dose-Response Relationship, Drug
* Drug Screening Assays, Antitumor
* Emodin
* Female
* Fluorouracil
* Humans
* Intracellular Signaling Peptides and Proteins
* MCF-7 Cells
* Neoplasm Proteins
* Protein Kinase Inhibitors
* Structure-Activity Relationship
* Tumor Cells, Cultured
|keywords=* 5-FU
* Emodin
* NRARP
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2018.09.045
}}
{{medline-entry
|title=Downregulation of [[FOXP1]] correlates with tendon stem/progenitor cells aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30170733
|abstract=Aging is known as a major risk factor for tendon disorders whereas the molecular mechanisms of age-related tendon disorders still remains unclear. Since tendon-derived stem/progenitor cells (TSPCs) play a vital role in tendon maintenance and healing, in this study we aimed to investigate the role of Forkhead box P1 ([[FOXP1]]) in aged TSPCs, we found that [[FOXP1]] mRNA and protein levels were markedly decreased in the aged TSPCs. Moreover, overexpression of [[FOXP1]] attenuates TSPCs aging, as confirmed by decreased of senescence-associated β-gal staining, as well as the senescence marker, p16 . Conversely, [[FOXP1]] depletion by siRNA promoted senescence in young TSPCs. Meanwhile, [[FOXP1]] overexpression also restores the age-associated reduction of self-renewal, migration and differentiation of TSPCs. In addition, [[FOXP1]] overexpression rescued decreased levels of [[E2F1]], pRb and cyclin D1 in aged TSPCs, which suggested that [[FOXP1]] regulates TSPCs aging through cellular senescence. These results indicate that [[FOXP1]] plays a crucial role in TSPCs aging.
|mesh-terms=* Animals
* Cell Cycle
* Cell Differentiation
* Cell Movement
* Cells, Cultured
* Cellular Senescence
* Down-Regulation
* Forkhead Transcription Factors
* Male
* Rats, Sprague-Dawley
* Repressor Proteins
* Stem Cells
* Tendons
|keywords=* Aging
* Cell cycle
* FOXP1
* Tendon-derived stem/progenitor cells
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2018.08.136
}}
{{medline-entry
|title=Loss of circadian protein [[TIMELESS]] accelerates the progression of cellular senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30100061
|abstract=[[TIMELESS]] protein is known to be essential for normal circadian rhythms. Aging is a deleterious process which affects all the physiological functions of complex organisms including the circadian rhythms. The circadian aging may produce disorganization among the circadian rhythms, arrhythmicity and even, disconnection from the environment, resulting in a detrimental situation to the organism. However, the role of circadian genes on the aging process is poorly understood. In present study, we found [[TIMELESS]] was down-regulated in cellular senescence, and further research indicated [[E2F1]] bound to the promotor of [[TIMELESS]] and regulated its expression in cellular senescence. Knockdown of [[TIMELESS]] accelerated cellular senescence induced by ectopic expression of RasV12, and overexpression of [[TIMELESS]] delayed this kind onset of senescence. Meanwhile, micrococcal nuclease assays proved depletion of [[TIMELESS]] exacerbated genomic instability at the onset of senescence. Together, our data reveal that [[TIMELESS]] plays a role in OIS, which is associated with genome stability changing.
|mesh-terms=* Cell Cycle Proteins
* Cell Line
* Cellular Senescence
* Circadian Rhythm
* E2F1 Transcription Factor
* Fibroblasts
* Gene Expression Regulation
* Genes, Reporter
* Genomic Instability
* HEK293 Cells
* Humans
* Hydrogen Peroxide
* Intracellular Signaling Peptides and Proteins
* Promoter Regions, Genetic
* Protein Binding
* RNA, Small Interfering
* Signal Transduction
* beta-Galactosidase
* ras Proteins
|keywords=* E2F1
* Senescence
* TIMELESS
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2018.08.040
}}
{{medline-entry
|title=Transcriptional Repression of High-Mobility Group Box 2 by p21 in Radiation-Induced Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29487276
|abstract=High mobility group box 2 ([[HMGB2]]) is an abundant, chromatin-associated, non-histone protein involved in transcription, chromatin remodeling, and recombination. Recently, the [[HMGB2]] gene was found to be significantly downregulated during senescence and shown to regulate the expression of senescent-associated secretory proteins. Here, we demonstrate that [[HMGB2]] transcription is repressed by p21 during radiation-induced senescence through the [[ATM]]-p53-p21 DNA damage signaling cascade. The loss of p21 abolished the downregulation of [[HMGB2]] caused by ionizing radiation, and the conditional induction of p21 was sufficient to repress the transcription of [[HMGB2]]. We also showed that the p21 protein binds to the [[HMGB2]] promoter region, leading to sequestration of RNA polymerase and transcription factors [[E2F1]], Sp1, and p300. In contrast, NF-Y, a CCAAT box-binding protein complex, is required for the expression of [[HMGB2]], but NF-Y binding to the [[HMGB2]] promoter was unaffected by either radiation or p21 induction. A proximity ligation assay results confirmed that the chromosome binding of [[E2F1]] and Sp1 was inhibited by p21 induction. As [[HMGB2]] have been shown to regulate premature senescence by IR, targeting the p21-mediated repression of [[HMGB2]] could be a strategy to overcome the detrimental effects of radiation-induced senescence.
|mesh-terms=* Adenocarcinoma
* Adenocarcinoma of Lung
* Ataxia Telangiectasia Mutated Proteins
* Cell Line, Tumor
* Cellular Senescence
* Colorectal Neoplasms
* Cyclin-Dependent Kinase Inhibitor p21
* DNA Damage
* Down-Regulation
* Fibroblasts
* HMGB2 Protein
* HT29 Cells
* Humans
* Lung Neoplasms
* Promoter Regions, Genetic
* Radiotherapy
* Transcription, Genetic
* Tumor Suppressor Protein p53
|keywords=* HMGB2
* p21
* radiation
* senescence
* transcription repression
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935093
}}
{{medline-entry
|title=Genome-wide association study and annotating candidate gene networks affecting age at first calving in Nellore cattle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28994157
|abstract=We performed a genome-wide mapping for the age at first calving (AFC) with the goal of annotating candidate genes that regulate fertility in Nellore cattle. Phenotypic data from 762 cows and 777k SNP genotypes from 2,992 bulls and cows were used. Single nucleotide polymorphism (SNP) effects based on the single-step GBLUP methodology were blocked into adjacent windows of 1 Megabase (Mb) to explain the genetic variance. SNP windows explaining more than 0.40% of the AFC genetic variance were identified on chromosomes 2, 8, 9, 14, 16 and 17. From these windows, we identified 123 coding protein genes that were used to build gene networks. From the association study and derived gene networks, putative candidate genes (e.g., [[PAPPA]], [[PREP]], [[FER1L6]], [[TPR]], [[NMNAT1]], [[ACAD10]], [[PCMTD1]], [[CRH]], OPKR1, [[NPBWR1]] and NCOA2) and transcription factors (TF) (STAT1, [[STAT3]], [[RELA]], [[E2F1]] and EGR1) were strongly associated with female fertility (e.g., negative regulation of luteinizing hormone secretion, folliculogenesis and establishment of uterine receptivity). Evidence suggests that AFC inheritance is complex and controlled by multiple loci across the genome. As several windows explaining higher proportion of the genetic variance were identified on chromosome 14, further studies investigating the interaction across haplotypes to better understand the molecular architecture behind AFC in Nellore cattle should be undertaken.
|mesh-terms=* Aging
* Animals
* Breeding
* Cattle
* Female
* Fertility
* Gene Regulatory Networks
* Genome-Wide Association Study
* Genotype
* Phenotype
* Polymorphism, Single Nucleotide
* Quantitative Trait Loci
|keywords=* beef cattle
* gene function
* single-step
|full-text-url=https://sci-hub.do/10.1111/jbg.12299
}}
{{medline-entry
|title=Triptolide Promotes Senescence of Prostate Cancer Cells Through Histone Methylation and Heterochromatin Formation
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28952292
|abstract=Background: Triptolide is a medicinal herb-derived diterpene triepoxide with potent anti-tumor activity, mainly
,correlated with its ability to inhibit and inactivate subunits of RNA polymerase II, thereby suppressing global gene
transcription. Epigenetic imbalance including histone methylation are well known to play important roles in prostate
cancer (PCa) onset and progression. The goal of this study was to investigate whether triptolide might exert anti-PCa
influence by reshaping the histone methylation landscape. Methods: Triptolide-treated PCa cell lines were analyzed by
RT-qPCR and western blotting for expression of histone demethylases and associated markers. Detection of senescence
was achieved using senescence associated β-galactosidase staining and analyses of apoptosis and cell cycle were
performed by flow cytometry. Senescence–associated heterochromatin foci were detected by immunofluorescence
while chromatin immunoprecipitation associated with qPCR (CHIP-qPCR) was applied to assess accumulation of
histone markers on promoters of target genes. Cell viability was determined using the [[CCK]]-8 assay. Results: We found
triptolide to enhance H3K27me3 levels by down-regulating JMJD3 and UTX and also H3K9me3 through up-regulation
of [[SUV39H1]]. Furthermore, it up-regulated expression of HP1α. Thereby, heterochromatin formation and deposition
on promoters of [[E2F1]]-target genes was promoted, correlating with suppression of gene transcription, decreased cell
viability and induction of a senescence-like phenotype in PCa cells. Conclusions: Our results indicate that triptolide
exerts anti-tumor effects including PCa cell senescence at least partially through increasing the levels of repressive
histone H3 methylation and formation of a repressive chromatin state in PCa cells. Further studies of its potential as
an epigenetic anti-PCa drug appear warranted.

|keywords=* Triptolide
* prostate cancer
* senescence
* Histone
* Methylation
* Heterochromatin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720660
}}
{{medline-entry
|title=Senescence-associated microRNAs target cell cycle regulatory genes in normal human lung fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28658612
|abstract=Senescence recapitulates the ageing process at the cell level. A senescent cell stops dividing and exits the cell cycle. MicroRNAs (miRNAs) acting as master regulators of transcription, have been implicated in senescence. In the current study we investigated and compared the expression of miRNAs in young versus senescent human fibroblasts (HDFs), and analysed the role of mRNAs expressed in replicative senescent HFL-1 HDFs. Cell cycle analysis confirmed that HDFs accumulated in G /S cell cycle phase. Nanostring analysis of isolated miRNAs from young and senescent HFL-1 showed that a distinct set of 15 miRNAs were significantly up-regulated in senescent cells including hsa-let-7d-5p, hsa-let-7e-5p, hsa-miR-23a-3p, hsa-miR-34a-5p, hsa-miR-122-5p, hsa-miR-125a-3p, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-181a-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-503-5p, hsa-miR-574-3p, hsa-miR-574-5p and hsa-miR-4454. Importantly, pathway analysis of miRNA target genes down-regulated during replicative senescence in a public RNA-seq data set revealed a significant high number of genes regulating cell cycle progression, both G /S and G /M cell cycle phase transitions and telomere maintenance. The reduced expression of selected miRNA targets, upon replicative and oxidative-stress induced senescence, such as the cell cycle effectors [[E2F1]], CcnE, Cdc6, CcnB1 and Cdc25C was verified at the protein and/or RNA levels. Induction of G1/S cell cycle phase arrest and down-regulation of cell cycle effectors correlated with the up-regulation of miR-221 upon both replicative and oxidative stress-induced senescence. Transient expression of miR-221/222 in HDFs promoted the accumulation of HDFs in G1/S cell cycle phase. We propose that miRNAs up-regulated during replicative senescence may act in concert to induce cell cycle phase arrest and telomere erosion, establishing a senescent phenotype.
|mesh-terms=* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Dose-Response Relationship, Drug
* Down-Regulation
* Fibroblasts
* Gene Expression
* Genes, cdc
* Humans
* Hydrogen Peroxide
* Lung
* MicroRNAs
* Oxidants
* Oxidative Stress
|keywords=* Cell cycle effectors
* Cellular senescence
* Human lung fibroblasts
* MicroRNAs
|full-text-url=https://sci-hub.do/10.1016/j.exger.2017.06.017
}}
{{medline-entry
|title=Neuronal tetraploidization in the cerebral cortex correlates with reduced cognition in mice and precedes and recapitulates Alzheimer's-associated neuropathology.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28494436
|abstract=A controversy exists as to whether de novo-generated neuronal tetraploidy (dnNT) occurs in Alzheimer's disease. In addition, the presence of age-associated dnNT in the normal brain remains unexplored. Here we show that age-associated dnNT occurs in both superficial and deep layers of the cerebral cortex of adult mice, a process that is blocked in the absence of [[E2F1]], a known regulator of cell cycle progression. This blockage correlates with improved cognition despite compromised neurogenesis in the adult hippocampus was confirmed in mice lacking the E2f1 gene. We also show that the human cerebral cortex contains tetraploid neurons. In normal humans, age-associated dnNT specifically occurs in the entorhinal cortex whereas, in Alzheimer, dnNT also affects association cortices prior to neurofibrillary tangle formation. Alzheimer-associated dnNT is likely potentiated by altered amyloid precursor protein ([[APP]]) processing as it is enhanced in the cerebral cortex of young [[APP]] /PS1  mice, long before the first amyloid plaques are visible in their brains. In contrast to age-associated dnNT, enhanced dnNT in [[APP]] /PS1  mice mostly affects the superficial cortical layers. The correlation of dnNT with reduced cognition in mice and its spatiotemporal course, preceding and recapitulating Alzheimer-associated neuropathology, makes this process a potential target for intervention in Alzheimer's disease.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Cell Cycle
* Cerebral Cortex
* Cognition
* E2F1 Transcription Factor
* Female
* Hippocampus
* Humans
* Male
* Mice, Transgenic
* Middle Aged
* Neurofibrillary Tangles
* Neurogenesis
* Neurons
* Tetraploidy
|keywords=* DNA content
* E2F1
* FISH
* Flow cytometry
* Memory
* β-Amyloid
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2017.04.008
}}
{{medline-entry
|title=Old age and the associated impairment of bones' adaptation to loading are associated with transcriptomic changes in cellular metabolism, cell-matrix interactions and the cell cycle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27840164
|abstract=In old animals, bone's ability to adapt its mass and architecture to functional load-bearing requirements is diminished, resulting in bone loss characteristic of osteoporosis. Here we investigate transcriptomic changes associated with this impaired adaptive response. Young adult (19-week-old) and aged (19-month-old) female mice were subjected to unilateral axial tibial loading and their cortical shells harvested for microarray analysis between 1h and 24h following loading (36 mice per age group, 6 mice per loading group at 6 time points). In non-loaded aged bones, down-regulated genes are enriched for MAPK, Wnt and cell cycle components, including [[E2F1]]. [[E2F1]] is the transcription factor most closely associated with genes down-regulated by ageing and is down-regulated at the protein level in osteocytes. Genes up-regulated in aged bone are enriched for carbohydrate metabolism, TNFα and TGFβ superfamily components. Loading stimulates rapid and sustained transcriptional responses in both age groups. However, genes related to proliferation are predominantly up-regulated in the young and down-regulated in the aged following loading, whereas those implicated in bioenergetics are down-regulated in the young and up-regulated in the aged. Networks of inter-related transcription factors regulated by [[E2F1]] are loading-responsive in both age groups. Loading regulates genes involved in similar signalling cascades in both age groups, but these responses are more sustained in the young than aged. From this we conclude that cells in aged bone retain the capability to sense and transduce loading-related stimuli, but their ability to translate acute responses into functionally relevant outcomes is diminished.
|mesh-terms=* Adaptation, Physiological
* Aging
* Animals
* Carbohydrate Metabolism
* Cell Cycle
* Cell Proliferation
* E2F1 Transcription Factor
* Energy Metabolism
* Extracellular Matrix
* Female
* Gene Regulatory Networks
* Humans
* Mice
* Mice, Inbred C57BL
* Osteocytes
* Signal Transduction
* Tibia
* Transcriptome
* Weight-Bearing
|keywords=* Ageing
* Bone
* Mechanical loading
* Proliferation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5139832
}}
{{medline-entry
|title=Rac1-Mediated DNA Damage and Inflammation Promote Nf2 Tumorigenesis but Also Limit Cell-Cycle Progression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27818180
|abstract=Merlin encoded by the Nf2 gene is a bona fide tumor suppressor that has been implicated in regulation of both the Hippo-Yap and Rac1-Pak1 pathways. Using genetically engineered murine liver models, we show that co-deletion of Rac1 with Nf2 blocks tumor initiation but paradoxically exacerbates hepatomegaly induced by Nf2 loss, which can be suppressed either by treatment with pro-oxidants or by co-deletion of Yap. Our results suggest that while Yap acts as the central driver of proliferation during Nf2 tumorigenesis, Rac1 primarily functions as an inflammation switch by inducing reactive oxygen species that, on one hand, induce nuclear factor κB signaling and expression of inflammatory cytokines, and on the other activate p53 checkpoint and senescence programs dampening the cyclin D1-pRb-[[E2F1]] pathway. Interestingly, senescence markers are associated with benign [[NF2]] tumors but not with malignant [[NF2]] mutant mesotheliomas, suggesting that senescence may underlie the benign nature of most [[NF2]] tumors.
|mesh-terms=* Animals
* Biomarkers
* Carcinogenesis
* Cell Cycle
* Cell Dedifferentiation
* Cell Proliferation
* Cellular Senescence
* DNA Damage
* Epithelial Cells
* Extracellular Signal-Regulated MAP Kinases
* Gene Deletion
* Hepatocytes
* Hepatomegaly
* Humans
* Inflammation
* Liver
* Meningioma
* Mice
* Mice, Knockout
* NF-kappa B
* Neurilemmoma
* Neurofibromin 2
* Organ Size
* Phenotype
* Proto-Oncogene Proteins c-akt
* Reactive Oxygen Species
* Signal Transduction
* Tumor Suppressor Protein p53
* rac1 GTP-Binding Protein
|keywords=* DNA damage response
* NF2
* ROS
* Rac1
* Yap
* inflammation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519326
}}
{{medline-entry
|title=The activation of [[OR51E1]] causes growth suppression of human prostate cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27374083
|abstract=The development of prostate cancer (PCa) is regulated by the androgen-dependent activity of the androgen receptor ([[AR]]). Androgen-deprivation therapy (ADT) is therefore the gold standard treatment to suppress malignant progression of PCa. Nevertheless, due to the development of castration resistance, recurrence of disease after initial response to ADT is a major obstacle to successful treatment. As G-protein coupled receptors play a fundamental role in PCa physiology, they might represent promising alternative or combinatorial targets for advanced diseases. Here, we verified gene expression of the olfactory receptors (ORs) [[OR51E1]] [prostate-specific G-protein coupled receptor 2 (PSGR2)] and [[OR51E2]] (PSGR) in human PCa tissue by RNA-Seq analysis and RT-PCR and elucidated the subcellular localization of both receptor proteins in human prostate tissue. The [[OR51E1]] agonist nonanoic acid (NA) leads to the phosphorylation of various protein kinases and growth suppression of the PCa cell line LNCaP. Furthermore, treatment with NA causes reduction of androgen-mediated [[AR]] target gene expression. Interestingly, NA induces cellular senescence, which coincides with reduced [[E2F1]] mRNA levels. In contrast, treatment with the structurally related compound 1-nonanol or the [[OR2AG1]] agonist amyl butyrate, neither of which activates [[OR51E1]], did not lead to reduced cell growth or an induction of cellular senescence. However, decanoic acid, another [[OR51E1]] agonist, also induces cellular senescence. Thus, our results suggest the involvement of [[OR51E1]] in growth processes of PCa cells and its impact on [[AR]]-mediated signaling. These findings provide novel evidences to support the functional importance of ORs in PCa pathogenesis.
|mesh-terms=* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Disease Progression
* Humans
* Male
* Neoplasm Proteins
* Phosphorylation
* Prostatic Neoplasms
* Prostatic Neoplasms, Castration-Resistant
* Receptors, Androgen
* Receptors, G-Protein-Coupled
* Signal Transduction
* Transfection
|keywords=* OR51E1
* androgen receptor
* cellular senescence
* proliferation
* prostate cancer
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217014
}}
{{medline-entry
|title=Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26873092
|abstract=Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo approaches. Using the approaches of molecular and cellular biology, we show that a circular RNA generated from a member of the forkhead family of transcription factors, Foxo3, namely circ-Foxo3, was highly expressed in heart samples of aged patients and mice, which was correlated with markers of cellular senescence. Doxorubicin-induced cardiomyopathy was aggravated by ectopic expression of circ-Foxo3 but was relieved by silencing endogenous circ-Foxo3. We also found that silencing circ-Foxo3 inhibited senescence of mouse embryonic fibroblasts and that ectopic expression of circ-Foxo3 induced senescence. We found that circ-Foxo3 was mainly distributed in the cytoplasm, where it interacted with the anti-senescent protein ID-1 and the transcription factor [[E2F1]], as well as the anti-stress proteins FAK and HIF1α. We conclude that ID-1, [[E2F1]], FAK, and HIF1α interact with circ-Foxo3 and are retained in the cytoplasm and could no longer exert their anti-senescent and anti-stress roles, resulting in increased cellular senescence.
|mesh-terms=* Aged
* Animals
* Antibiotics, Antineoplastic
* Cell Line
* Cellular Senescence
* Doxorubicin
* E2F1 Transcription Factor
* Focal Adhesion Kinase 1
* Forkhead Box Protein O3
* Humans
* Hypoxia-Inducible Factor 1, alpha Subunit
* Inhibitor of Differentiation Protein 1
* Mice
* Protein Transport
* RNA
* RNA, Circular
* Stress, Physiological
|keywords=* Circular RNA
* Foxo3
* Heart senescence
* Stress response
|full-text-url=https://sci-hub.do/10.1093/eurheartj/ehw001
}}
{{medline-entry
|title=[[CBX8]] antagonizes the effect of Sirtinol on premature senescence through the AKT-RB-[[E2F1]] pathway in K562 leukemia cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26718407
|abstract=Although tyrosine kinase inhibitor (TKI) therapies are highly effective in the treatment of chronic myeloid leukemia (CML), frequent recurrence limits their usage and demands new approaches for CML therapy. Stress-induced premature senescence (SIPS) is considered a potential anticancer treatment, but the underlying mechanism remains elusive. Here, we report that Sirtinol, a known [[SIRT1]] inhibitor, induces premature senescence and growth arrest in K562 CML cells. Chromobox homolog 8 ([[CBX8]]) suppresses the Sirtinol-induced premature senescence, which is reversed by [[CBX8]] knockdown. Upon Sirtinol treatment, the phosphorylation of [[AKT1]], p27KIP1 and RB is severely downregulated. However, [[CBX8]] overexpression enhances phosphorylation and, thereby, promotes the transcriptional activity of [[E2F1]], both of which are impaired upon CBX depletion. These data suggest that [[CBX8]] modulates SIPS through the RB-[[E2F1]] pathway in CML cells and provide important insight into its application in CML treatment. 
|mesh-terms=* Antineoplastic Agents
* Benzamides
* Cell Cycle Checkpoints
* Cellular Senescence
* Drug Antagonism
* E2F1 Transcription Factor
* Humans
* K562 Cells
* Leukemia, Myelogenous, Chronic, BCR-ABL Positive
* Naphthols
* Oncogene Protein v-akt
* Polycomb Repressive Complex 1
* Retinoblastoma Protein
* Signal Transduction
|keywords=* CBX8
* Leukemia
* Premature senescence
* RB-E2F1
* SIRT1
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2015.12.070
}}
{{medline-entry
|title=Nucleolar repression facilitates initiation and maintenance of senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26505814
|abstract=Tumor cells with defective apoptosis pathways often respond to chemotherapy by entering irreversible cell cycle arrest with features of senescence. However, rare cells can bypass entry to senescence, or re-enter cell cycle from a senescent state. Deficiency in senescence induction and maintenance may contribute to treatment resistance and early relapse after therapy. Senescence involves epigenetic silencing of cell cycle genes and reduced rRNA transcription. We found that senescence-inducing treatments such as DNA damage and RNA polymerase I inhibition stimulate the binding between the nucleolar protein NML (nucleomethylin) and SirT1. The NML complex promotes rDNA heterochromatin formation and represses rRNA transcription. Depletion of NML reduced the levels of H3K9Me3 and H3K27Me3 heterochromatin markers on rDNA and [[E2F1]] target promoters in senescent cells, increased rRNA transcription, and increased the frequency of cell cycle re-entry. Depletion of the nucleolar transcription repressor factor TIP5 also promoted escape from senescence. Furthermore, tumor tissue staining showed that breast tumors without detectable nucleolar NML expression had poor survival. The results suggest that efficient regulation of nucleolar rDNA transcription facilitates the maintenance of irreversible cell cycle arrest in senescent cells. Deficiency in nucleolar transcription repression may accelerate tumor relapse after chemotherapy. 
|mesh-terms=* Apoptosis
* Breast Neoplasms
* Cell Cycle Checkpoints
* Cell Line, Tumor
* Cell Nucleolus
* Cellular Senescence
* Chromatin Assembly and Disassembly
* Chromosomal Proteins, Non-Histone
* DNA, Ribosomal
* E2F1 Transcription Factor
* Epigenesis, Genetic
* Female
* Heterochromatin
* Histones
* Humans
* Male
* Methyltransferases
* Nuclear Proteins
* Promoter Regions, Genetic
* Protein Binding
* RNA Polymerase I
* RNA, Ribosomal
* RNA-Binding Proteins
* Signal Transduction
* Sirtuin 1
* Transcription, Genetic
* Urinary Bladder Neoplasms
|keywords=* NML
* chemotherapy
* heterochromatin
* nucleolus
* p53
* rDNA
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825723
}}
{{medline-entry
|title=Targeted gene mutation of [[E2F1]] evokes age-dependent synaptic disruption and behavioral deficits.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24460902
|abstract=Aberrant expression and activation of the cell cycle protein [[E2F1]] in neurons has been implicated in many neurodegenerative diseases. As a transcription factor regulating G1 to S phase progression in proliferative cells, [[E2F1]] is often up-regulated and activated in models of neuronal death. However, despite its well-studied functions in neuronal death, little is known regarding the role of [[E2F1]] in the mature brain. In this study, we used a combined approach to study the effect of [[E2F1]] gene disruption on mouse behavior and brain biochemistry. We identified significant age-dependent olfactory and memory-related deficits in E2f1 mutant mice. In addition, we found that [[E2F1]] exhibits punctated staining and localizes closely to the synapse. Furthermore, we found a mirroring age-dependent loss of post-synaptic protein-95 in the hippocampus and olfactory bulb as well as a global loss of several other synaptic proteins. Coincidently, [[E2F1]] expression is significantly elevated at the ages, in which behavioral and synaptic perturbations were observed. Finally, we show that deficits in adult neurogenesis persist late in aged E2f1 mutant mice which may partially contribute to the behavior phenotypes. Taken together, our data suggest that the disruption of [[E2F1]] function leads to specific age-dependent behavioral deficits and synaptic perturbations. [[E2F1]] is a transcription factor regulating cell cycle progression and apoptosis. Although [[E2F1]] dysregulation under toxic conditions can lead to neuronal death, little is known about its physiologic activity in the healthy brain. Here, we report significant age-dependent olfactory and memory deficits in mice with dysfunctional [[E2F1]]. Coincident with these behavioral changes, we also found age-matched synaptic disruption and persisting reduction in adult neurogenesis. Our study demonstrates that [[E2F1]] contributes to physiologic brain structure and function. 
|mesh-terms=* Aging
* Animals
* Behavior, Animal
* Blotting, Western
* Cells, Cultured
* E2F1 Transcription Factor
* Gene Targeting
* Image Processing, Computer-Assisted
* Immunohistochemistry
* Memory
* Mice, Inbred C57BL
* Motor Activity
* Mutation
* Odorants
* Olfaction Disorders
* Postural Balance
* Psychomotor Performance
* Rats
* Rats, Sprague-Dawley
* Recognition, Psychology
* Smell
* Synapses
* Synaptosomes
|keywords=* E2F
* adult neurogenesis
* cell cycle
* synaptic proteins
* transgenic mice
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028376
}}
{{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=Prolonged autophagy by [[MTOR]] inhibitor leads radioresistant cancer cells into senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23989658
|abstract=Radiotherapy is one of the well-established therapeutic modalities for cancer treatment. However, the emergence of cells refractory to radiation is a major obstacle to successful treatment with radiotherapy. Many reports suggest that inhibitors targeting the mechanistic target of rapamycin ([[MTOR]]) can sensitize cancer cells to the effect of radiation, although by which mechanism [[MTOR]] inhibitors enhance the efficacy of radiation toward cancer cells remains to be elucidated. Our studies indicate that a potent and persistent activation of autophagy via inhibition of the [[MTOR]] pathway, even in cancer cells where autophagy is occurring, can trigger premature senescence, cellular proliferation arrest. Combined treatment of [[MTOR]] inhibitor and radiation induce heterochromatin formation, an irreversible growth arrest and an increase of senescence-associated [[GLB1]] (β-galactosidase) activity, which appear to result from a constant activation of [[TP53]] and a restoration in the activity of retinoblastoma 1 protein (RB1)-[[E2F1]]. Thus, this study provides evidence that promoting cellular senescence via inhibition of the [[MTOR]] pathway may serve as an avenue to augment radiosensitivity in cancer cells that initiate an autophagy-survival mode to radiotherapy. 
|mesh-terms=* Animals
* Autophagy
* Cell Proliferation
* Cellular Senescence
* Humans
* Neoplasms
* Radiation Tolerance
* Retinoblastoma Protein
* TOR Serine-Threonine Kinases
|keywords=* MTOR inhibitor
* RB
* autophagy
* cellular senescence
* irradiation
|full-text-url=https://sci-hub.do/10.4161/auto.25879
}}
{{medline-entry
|title=[[E2F1]] in renal cancer: Mr Hyde disguised as Dr Jekyll?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23868058
|abstract=The transcription factor [[E2F1]] has both oncogenic and tumour suppressor properties, depending on the context. Clarifying the function of [[E2F1]] in different types of cancer is relevant because in those situations in which it acts as an oncogene there may be a route for therapeutic interference. Renal cell carcinoma is the most frequent form of kidney cancer in adults and inactivation of the von Hippel-Lindau ([[VHL]]) gene underlies most cases. This malignancy represents a challenge for standard therapies due to drug- and radio-resistance, effects that fit well within the scope of functions of [[E2F1]]. A new report by Mans et al postulates that up-regulation of [[E2F1]] in [[VHL]]-defective renal cell carcinoma induces cell senescence and can thus be considered a good prognostic factor. Here we discuss these findings in a wider context and propose that [[E2F1]] may actually not play a uniform role in renal cell carcinoma but rather an ambiguous one whose deeper understanding could have practical implications.
|mesh-terms=* Animals
* Carcinoma, Renal Cell
* E2F1 Transcription Factor
* Humans
* Kidney Neoplasms
|keywords=* E2F1
* HIF
* VHL
* cell cycle
* p27
* renal cell carcinoma
* senescence
|full-text-url=https://sci-hub.do/10.1002/path.4238
}}
{{medline-entry
|title=Neuronal cell cycle re-entry markers are altered in the senescence accelerated mouse P8 (SAMP8).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22451322
|abstract=Senescence-accelerated mice 8 (SAMP8), a model of aging, display many established pathological features of Alzheimer's disease (AD); however, whether cell cycle alterations exist in these animals remains unknown. Given that these animals present changes such as tau phosphorylation and redox imbalance, both associated with cell cycle alterations, we determined whether changes in cell cycle markers were present in SAMP8 and SAMR1 (control strain) at 3, 6, and 9 months-old brains. As expected, an increase in tau hyperphosphorylation and its associated machinery, i.e., cdk5 and GSK3β, was observed both between strains and also with aging. Particularly, significant differences in cyclin A, cyclin D1, cyclin E, Cdk2, cyclin B, pR, and [[E2F1]] were found when comparing SAMP8 to SAMR1. More interestingly, a partial correlation with several cell cycle markers described in AD brain is found in SAMP8, indicating that some specific hallmarks of AD are also present in this strain, which has been postulated as an early switch model of the disease.
|mesh-terms=* Aging
* Animals
* Biomarkers
* Cell Cycle
* Cell Cycle Checkpoints
* Cyclin-Dependent Kinase 5
* Glycogen Synthase Kinase 3
* Glycogen Synthase Kinase 3 beta
* Male
* Mice
* Models, Animal
* Neurons
* Phosphorylation
* tau Proteins

|full-text-url=https://sci-hub.do/10.3233/JAD-2012-120112
}}
{{medline-entry
|title=Mediator subunits [[MED1]] and [[MED24]] cooperatively contribute to pubertal mammary gland development and growth of breast carcinoma cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22331469
|abstract=The Mediator subunit [[MED1]] is essential for mammary gland development and lactation, whose contribution through direct interaction with estrogen receptors (ERs) is restricted to involvement in pubertal mammary gland development and luminal cell differentiation. Here, we provide evidence that the [[MED24]]-containing submodule of Mediator functionally communicates specifically with [[MED1]] in pubertal mammary gland development. Mammary glands from [[MED1]]/[[MED24]] double heterozygous knockout mice showed profound retardation in ductal branching during puberty, while single haploinsufficient glands developed normally. DNA synthesis of both luminal and basal cells were impaired in double mutant mice, and the expression of ER-targeted genes encoding [[E2F1]] and cyclin D1, which promote progression through the G(1)/S phase of the cell cycle, was attenuated. Luciferase reporter assays employing double mutant mouse embryonic fibroblasts showed selective impairment in ER functions. Various breast carcinoma cell lines expressed abundant amounts of [[MED1]], [[MED24]], and [[MED30]], and attenuated expression of [[MED1]] and [[MED24]] in breast carcinoma cells led to attenuated DNA synthesis and growth. These results indicate functional communications between the [[MED1]] subunit and the [[MED24]]-containing submodule that mediate estrogen receptor functions and growth of both normal mammary epithelial cells and breast carcinoma cells.
|mesh-terms=* Aging
* Animals
* Breast Neoplasms
* Cell Line, Tumor
* Cyclin D1
* E2F1 Transcription Factor
* Female
* G1 Phase
* Humans
* Mammary Glands, Animal
* Mammary Neoplasms, Animal
* Mediator Complex
* Mediator Complex Subunit 1
* Mice
* S Phase

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318591
}}
{{medline-entry
|title=Mutant mouse models reveal the relative roles of [[E2F1]] and [[E2F3]] in vivo.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/11909960
|abstract=The [[E2F1]], -2, and -3 transcription factors are key downstream targets of the retinoblastoma protein (pRB) tumor suppressor that drive expression of proliferation-associated genes. Here we use mutant mouse strains to investigate [[E2F3]]'s role in vivo. We show that [[E2F3]] is essential for embryonic viability in the pure 129/Sv background but the presence of C57BL/6 alleles yields some adult survivors. Although growth retarded, surviving E2f3(-/-) animals are initially healthy. However, they die prematurely, exhibiting no obvious tumor phenotype but with the typical signs of congestive heart failure. The defects are completely distinct from those arising in E2f1 mutant mice (S. J. Field et al., Cell 85:549-561; 1996; L. Yamasaki et al., Cell 85:537-548, 1996), supporting the prevailing view that these E2Fs must have some unique biological functions in vivo. To test this model, we examined the phenotypes of E2f1 E2f3 compound mutant mice. Almost all of the developmental and age-related defects arising in the individual E2f1 or E2f3 mice were exacerbated by the mutation of the other E2f. Thus, [[E2F1]] and [[E2F3]] appear to play critical, overlapping roles in the development and maintenance of a variety of tissues. Importantly, this study did identify one major difference in the properties of [[E2F1]] and [[E2F3]]: either alone or in combination with [[E2F1]] loss, E2f3 mutation did not increase the incidence of tumor formation. These data strongly suggest that tumor suppression is a specific property of [[E2F1]] and not [[E2F3]].
|mesh-terms=* Aging
* Animals
* Animals, Newborn
* Cell Cycle Proteins
* DNA-Binding Proteins
* E2F Transcription Factors
* E2F1 Transcription Factor
* E2F3 Transcription Factor
* Embryonic and Fetal Development
* Female
* Heart Failure
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Mice, Mutant Strains
* Models, Cardiovascular
* Neoplasms, Experimental
* Phenotype
* Transcription Factors

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC133738
}}
{{medline-entry
|title=[Aging and cellular senescence].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/7616677
|abstract=Mechanisms of aging involve genetic programs and error accumulation. Cellular aging is an aspect of organismal aging from a point of view of age-dependent declines of tissue cells during the postreproductive aging process and a parallelism between enhanced individual and cellular aging in some genetic progeroid syndromes. Cellular senescence involves the gene-directed inhibition of replicative potential of cells. Cell fusion analysis has indicated that senescent normal and presenescent Werner syndrome cells cause the dominant suppression of DNA synthesis in the partner of either actively growing cells or any cells of the four complementation groups of immortalized human cells. Membrane proteins produced in senescent cells showed the biphasic DNA synthesis-inhibiting activity when assayed for young cells. Senescent cells showed the strong transcriptional repressions of early serum responsive genes (c-fos, c-jun, c-myc), late responsive genes of transcription factor [[E2F1]] and cyclin E. In addition, the protein levels of [[CDK2]] and cyclin E are also extremely low, with an increased level of the p53-dependent p21 Cip 1 protein which inhibits the kinase activity of cyclins/CDKs by forming complexes. Such characteristic molecular factors and mechanisms feature irreversible G1-arrest in cellular senescence.
|mesh-terms=* Aging
* Cellular Senescence
* Humans

|full-text-url=https://sci-hub.do/10.3143/geriatrics.32.259
}}