Редактирование: CDK2

Cyclin-dependent kinase 2 (EC 2.7.11.22) (Cell division protein kinase 2) (p33 protein kinase) [CDKN2]

==Publications==

{{medline-entry
|title=Babam2 Regulates Cell Cycle Progression and Pluripotency in Mouse Embryonic Stem Cells as Revealed by Induced DNA Damage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33050379
|abstract=BRISC and [[BRCA1]]-A complex member 2 ([i]Babam2[/i]) plays an essential role in promoting cell cycle progression and preventing cellular senescence. [i]Babam2[/i]-deficient fibroblasts show proliferation defect and premature senescence compared with their wild-type (WT) counterpart. Pluripotent mouse embryonic stem cells (mESCs) are known to have unlimited cell proliferation and self-renewal capability without entering cellular senescence. Therefore, studying the role of [i]Babam2[/i] in ESCs would enable us to understand the mechanism of [i]Babam2[/i] in cellular aging, cell cycle regulation, and pluripotency in ESCs. For this study, we generated [i]Babam2[/i] knockout ([i]Babam2[/i] ) mESCs to investigate the function of [i]Babam2[/i] in mESCs. We demonstrated that the loss of [i]Babam2[/i] in mESCs leads to abnormal G1 phase retention in response to DNA damage induced by gamma irradiation or doxorubicin treatments. Key cell cycle regulators, [[CDC25A]] and [[CDK2]], were found to be degraded in [i]Babam2[/i]  mESCs following gamma irradiation. In addition, [i]Babam2[/i]  mESCs expressed p53 strongly and significantly longer than in control mESCs, where p53 inhibited Nanog expression and G1/S cell cycle progression. The combined effects significantly reduced developmental pluripotency in [i]Babam2[/i]  mESCs. In summary, [i]Babam2[/i] maintains cell cycle regulation and pluripotency in mESCs in response to induced DNA damage.

|keywords=* Babam2
* DNA damage
* cell cycle
* embryonic stem cells
* pluripotency
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600899
}}
{{medline-entry
|title=Guilu Erxian Glue () Inhibits Chemotherapy-Induced Bone Marrow Hematopoietic Stem Cell Senescence in Mice May via p16 -Rb Signaling Pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32915425
|abstract=To evaluate the effect of Guilu Erxian Glue (, GEG) on cyclophosphamide (CTX)-induced bone marrow hematopoietic stem cells (HSCs) senescence in mice and explore the underlying mechanism. The H  liver cancer ascites lump model was established in male Kunming mice by injecting intraperitoneally (i.p.) with 5 × 10 /mL H  cells per mouse. Fifty tumor-bearing mice were divided into the control, model, pifithrin-α, GEG, and GEG pifithrin-α groups using a random number table, 10 mice in each group. CTX (100 mg/kg i.p.) was administrated to mice from day 1 to day 3 (d1-d3) continuously except for the control group. The mice in the pifithrin-α, GEG and GEG pifithrin-α groups were treated with pifithrin-α (2.2 mg/(kg·d) i.p.) for 6 consecutive days (d4-d9), GEG (9.5 g/(kg·d) i.p.) for 9 consecutive days (d1-d9), and GEG plus pifithrin-α, respectively. HSCs were collected after 9-d drug treatment. The anti-aging effect of GEG was studied by cell viability, cell cycle, and β -galactosidase (β -gal) assays. The mRNA and protein expressions of cyclin-dependent kinase 2 ([[CDK2]]), [[CDK4]], inhibitor of cyclin-dependent kinase 4a encoding the tumor suppressor protein p16 (p16 ), p21 , p53, and phosphorylated retinoblastoma (pRb) were evaluated by quantitative real-time reverse transcription-polymerase chain reaction and semi-quantitative Western blot, respectively. Compared with the model group, GEG increased cell viability as well as proliferation (P<0.05 or P<0.01) and reduced β -gal expression. Furthermore, GEG significantly decreased the expressions of p16 , p53 and p21  proteins, and increased the expressions of [[CDK2]], [[CDK4]] and pRb proteins compared with the model group (P<0.05 or P<0.01). GEG can alleviate CTX-induced HSCs senescence in mice, and the p16 -Rb signaling pathway might be the underlying mechanism.

|keywords=* Chinese medicine
* Guilu Erxian Glue
* bone marrow suppression
* hematopoietic stem cell senescence
* p16INK4a
|full-text-url=https://sci-hub.do/10.1007/s11655-020-3098-3
}}
{{medline-entry
|title=p57  is a master regulator of human adipose derived stem cell quiescence and senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32224418
|abstract=Although human adipose derived stem cells (hADSCs) hold great promises for regenerative medicine, their key biological properties remain poorly understood. In particular, proliferation defects resulted from deep quiescence (dormancy) and senescence represent a major hurdle in hADSC production and clinical application. We have developed a model system for mechanistic dissection of hADSC quiescence and senescence. p57 , a major CDK inhibitor, was highly expressed in quiescent and senescent hADSCs but its level quickly declined upon stem cell activation. p57  overexpression induced quiescence in spite of proliferative signals and its knockdown promoted cell cycle reentry even with induction of quiescence presumably through modulating the [[CDK2]]-CyclinE1 complex. Given its key role in quiescence and senescence, p57  may be exploited for innovative strategies to amplify hADSCs of high quality for clinics.

|keywords=* Human adipose derived stem cells
* Quiescence
* Senescence
* p57(Kip2)
|full-text-url=https://sci-hub.do/10.1016/j.scr.2020.101759
}}
{{medline-entry
|title=Etoposide Induces Mitochondrial Dysfunction and Cellular Senescence in Primary Cultured Rat Astrocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31646843
|abstract=Brain aging is an inevitable process characterized by structural and functional changes and is a major risk factor for neurodegenerative diseases. Most brain aging studies are focused on neurons and less on astrocytes which are the most abundant cells in the brain known to be in charge of various functions including the maintenance of brain physical formation, ion homeostasis, and secretion of various extracellular matrix proteins. Altered mitochondrial dynamics, defective mitophagy or mitochondrial damages are causative factors of mitochondrial dysfunction, which is linked to age-related disorders. Etoposide is an anti-cancer reagent which can induce DNA stress and cellular senescence of cancer cell lines. In this study, we investigated whether etoposide induces senescence and functional alterations in cultured rat astrocytes. Senescence-associated β-galactosidase (SA-β-gal) activity was used as a cellular senescence marker. The results indicated that etoposide-treated astrocytes showed cellular senescence phenotypes including increased SA-β-gal-positive cells number, increased nuclear size and increased senescence-associated secretory phenotypes (SASP) such as IL-6. We also observed a decreased expression of cell cycle markers, including Phospho- Histone H3/Histone H3 and [[CDK2]], and dysregulation of cellular functions based on wound-healing, neuronal protection, and phagocytosis assays. Finally, mitochondrial dysfunction was noted through the determination of mitochondrial membrane potential using tetramethylrhodamine methyl ester (TMRM) and the measurement of mitochondrial oxygen consumption rate (OCR). These data suggest that etoposide can induce cellular senescence and mitochondrial dysfunction in astrocytes which may have implications in brain aging and neurodegenerative conditions.

|keywords=* Astrocytes
* Cellular Senescence
* Energy homeostasis
* Mitochondria
* Phagocytosis
* Wound Healing
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824621
}}
{{medline-entry
|title=Induction of Senescence in Cancer Cells by a Novel Combination of Cucurbitacin B and Withanone: Molecular Mechanism and Therapeutic Potential.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31112603
|abstract=Cancer, an uncontrolled proliferation syndrome, is treated with synthetic chemotherapeutic drugs that are associated with severe adverse effects. Development and application of new natural compounds is warranted to deal with the exponentially increasing incidence of cancer worldwide. Keeping selective toxicity to cancer cells as a priority criterion, we developed a combination of Cucurbitacin B and Withanone, and analyzed its anticancer potential using non-small cell lung cancer cells. We demonstrate that the selective cytotoxicity of the combination, called CucWi-N, to cancer cells is mediated by induction of cellular senescence that was characterized by decrease in Lamin A/C, [[CDK2]], [[CDK4]], Cyclin D, Cyclin E, phosphorylated RB, mortalin and increase in p53 and [[CARF]] proteins. It compromised cancer cell migration that was mediated by decrease in mortalin, hnRNP-K, vascular endothelial growth factor, matrix metalloproteinase 2, and fibronectin. We provide in silico, molecular dynamics and experimental data to support that CucWi-N (i) possesses high capability to target mortalin-p53 interaction and hnRNP-K proteins, (ii) triggers replicative senescence and inhibits metastatic potential of the cancer cells, and (iii) inhibits tumor progression and metastasis in vivo. We propose that CucWi-N is a potential natural anticancer drug that warrants further mechanistic and clinical studies.

|keywords=* Anticancer
* Antimetastatic
* Cucurbitacin B
* Senescence
* Withanone
|full-text-url=https://sci-hub.do/10.1093/gerona/glz077
}}
{{medline-entry
|title=Cyclin-Dependent Kinase 2 in Cellular Senescence and Cancer. A Structural and Functional Review.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30516105
|abstract=Cyclin-dependent kinase 2 ([[CDK2]]) has been studied due to its role in the cell-cycle progression. The elucidation of the [[CDK2]] structure paved the way to investigate the molecular basis for inhibition of this enzyme, with the coordinated efforts combining crystallography with functional studies. Our goal here is to review recent functional and structural studies directed to understanding the role of [[CDK2]] in cancer and senescence. There are over four hundreds of crystallographic structures available for [[CDK2]], many of them with binding affinity information. We use this abundance of data to analyze the essential features responsible for the inhibition of [[CDK2]] and its function in cancer and senescence. The structural and affinity data available [[CDK2]] makes it possible to have a clear view of the vital [[CDK2]] residues involved in molecular recognition. A detailed description of the structural basis for ligand binding is of pivotal importance in the design of [[CDK2]] inhibitors. Our analysis shows the relevance of the residues Leu 83 and Asp 86 for binding affinity. The recent findings revealing the participation of [[CDK2]] inhibition in senescence open the possibility to explore the richness of structural and affinity data for a new era in the development of [[CDK2]] inhibitors, targeting cellular senescence. Here, we analyzed structural information for [[CDK2]] in combination with inhibitors and mapped the molecular aspects behind the strongest [[CDK2]] inhibitors for which structures and ligandbinding affinity data were available. From this analysis, we identified the significant intermolecular interactions responsible for binding affinity. This knowledge may guide the future development of [[CDK2]] inhibitors targeting cancer and cellular senescence.
|mesh-terms=* Asparagine
* Binding Sites
* Cellular Senescence
* Crystallography, X-Ray
* Cyclin-Dependent Kinase 2
* Drug Design
* Humans
* Leucine
* Models, Molecular
* Neoplasms
* Protein Kinase Inhibitors
|keywords=* CDK2
* cancer
* cellular senescence
* cyclin
* drug design
* protein-ligand interactions.
|full-text-url=https://sci-hub.do/10.2174/1389450120666181204165344
}}
{{medline-entry
|title=Tenovin-1 Induces Senescence and Decreases Wound-Healing Activity in Cultured Rat Primary Astrocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30092626
|abstract=Brain aging induces neuropsychological changes, such as decreased memory capacity, language ability, and attention; and is also associated with neurodegenerative diseases. However, most of the studies on brain aging are focused on neurons, while senescence in astrocytes has received less attention. Astrocytes constitute the majority of cell types in the brain and perform various functions in the brain such as supporting brain structures, regulating blood-brain barrier permeability, transmitter uptake and regulation, and immunity modulation. Recent studies have shown that [[SIRT1]] and [[SIRT2]] play certain roles in cellular senescence in peripheral systems. Both [[SIRT1]] and [[SIRT2]] inhibitors delay tumor growth [i]in vivo[/i] without significant general toxicity. In this study, we investigated the role of tenovin-1, an inhibitor of [[SIRT1]] and [[SIRT2]], on rat primary astrocytes where we observed senescence and other functional changes. Cellular senescence usually is characterized by irreversible cell cycle arrest and induces senescence- associated β-galactosidase (SA-β-gal) activity. Tenovin-1-treated astrocytes showed increased SA-β-gal-positive cell number, senescence-associated secretory phenotypes, including [i]IL-6[/i] and [i]IL-1β[/i], and cell cycle-related proteins like phospho-histone H3 and [[CDK2]]. Along with the molecular changes, tenovin-1 impaired the wound-healing activity of cultured primary astrocytes. These data suggest that tenovin-1 can induce cellular senescence in astrocytes possibly by inhibiting [[SIRT1]] and [[SIRT2]], which may play particular roles in brain aging and neurodegenerative conditions.

|keywords=* Astrocyte
* Cellular senescence
* Senescence-associated secretory phenotype
* Tenovin-1
* Wound healing
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513186
}}
{{medline-entry
|title=Relationship between intermuscular adipose tissue infiltration and myostatin before and after aerobic exercise training.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29718700
|abstract=Intermuscular adipose tissue (IMAT) is associated with impaired skeletal muscle contractile and metabolic function. Myostatin and downstream signaling proteins such as cyclin-dependent kinase 2 ([[CDK2]]) contribute to the regulation of adipose and skeletal muscle mass in cell culture and animals models, but this relationship remains incompletely understood in humans. The purpose of this study was to determine if the infiltration of IMAT was associated with skeletal muscle myostatin and downstream proteins before and after 12 wk of aerobic exercise training (AET) in healthy older women (OW; 69 ± 2 yr), older men (OM; 74 ± 3 yr), and young men (YM; 20 ± 1 yr). We found that the infiltration of IMAT was correlated with myostatin and phosphorylated [[CDK2]] at tyrosine 15 [P-[[CDK2]](Tyr15)]. IMAT infiltration was greater in the older subjects and was associated with lower skeletal muscle function and exercise capacity. After 12 wk of AET, there was no change in body weight. Myostatin and P-[[CDK2]](Tyr15) were both decreased after AET, and the reduction in myostatin was associated with decreased IMAT infiltration. The decrease in myostatin and IMAT occurred concomitantly with increased exercise capacity, skeletal muscle size, and function after AET. These findings demonstrate that the reduction in IMAT infiltration after AET in weight stable individuals was accompanied by improvements in skeletal muscle function and exercise capacity. Moreover, the association between myostatin and IMAT was present in the untrained state and in response to exercise training, strengthening the potential regulatory role of myostatin on IMAT.
|mesh-terms=* Adipose Tissue
* Adiposity
* Age Factors
* Aged
* Bicycling
* Biomarkers
* Biopsy
* Cyclin-Dependent Kinase 2
* Exercise
* Exercise Test
* Female
* Humans
* Magnetic Resonance Imaging
* Male
* Muscle Contraction
* Muscle Strength
* Muscle, Skeletal
* Myostatin
* Phosphorylation
* Sedentary Behavior
* Time Factors
* Young Adult
|keywords=* IMAT
* aging
* hypertrophy
* noncontractile tissue
* skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734080
}}
{{medline-entry
|title=Carvacrol nanoemulsion evokes cell cycle arrest, apoptosis induction and autophagy inhibition in doxorubicin resistant-A549 cell line.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29405784
|abstract=Carvacrol is a monoterpenoid flavonoid found abundantly in thyme plants. Its physiochemical instability and partial solubility in water is the principal limitation for its industrial use. Hence, we made a carvacrol nanoemulsion (CANE) using ultrasonication method and characterized it by dynamic light scattering (DLS) technique which revealed a negative surface charge (-29.89 mV) with 99.1 nm average droplet size. CANE effectively induced apoptosis in doxorubicin-resistant A549 lung carcinoma cells (A549 ) evident by the elevated expression of apoptotic proteins such as Bax, Cytochrome C, and Cleaved caspase 3 and 9. Also, CANE displayed cell senescence leading to cell cycle arrest by reducing [[CDK2]], [[CDK4]], [[CDK6]], Cyclin E, Cyclin D1 and enhancing p21 protein expression. In addition, a potential role of CANE in the inhibition of autophagy was noted by evaluating the reduced conversion of LC-3 I to II. Beside this, a down-regulation of important autophagy markers [[ATG5]] and [[ATG7]] and upregulation of p62 were detected in response to CANE. We conclude that the synthesized CANE has potential to cause cell senescence, cell cycle arrest, autophagy inhibition and apoptosis in A549  cells and could be used as a potential candidate for lung cancer therapy.
|mesh-terms=* A549 Cells
* Animals
* Apoptosis
* Autophagy
* Cell Cycle Checkpoints
* Cellular Senescence
* Cymenes
* Dose-Response Relationship, Drug
* Doxorubicin
* Drug Resistance, Neoplasm
* Emulsions
* Humans
* Mice
* Mitochondria
* Monoterpenes
* Nanostructures
* Oxidative Stress
* Xenograft Model Antitumor Assays
|keywords=* Carvacrol nanoemulsion
* apoptosis
* autophagy
* cell senescence
|full-text-url=https://sci-hub.do/10.1080/21691401.2018.1434187
}}
{{medline-entry
|title=Gut flora-dependent metabolite Trimethylamine-N-oxide accelerates endothelial cell senescence and vascular aging through oxidative stress.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29325896
|abstract=Trimethylamine-N-oxide (TMAO), gut microbiota-dependent metabolites, has been shown to be associated with cardiovascular diseases. However, little is known about the relationship between TMAO and vascular aging. Here, we observed a change in TMAO during the aging process and the effects of TMAO on vascular aging and endothelial cell (EC) senescence. We analyzed age-related plasma levels of TMAO in young adults (18-44 years old), older adults (≥ 65 years old), and 1-month-old, 3-month-old, 6-month-old and 10-month-old senescence-accelerated mouse prone 8 (SAMP8) and age-matched senescence-accelerated mouse resistance 1 (SAMR1) models. We found that circulating TMAO increased with age both in humans and mice. Next, we observed that a TMAO treatment for 16 weeks induced vascular aging in SAMR1 mice and accelerated the process in SAMP8 mice, as measured by an upregulation of senescence markers including senescence-associated β-galactosidase (SA-β-gal), p53, and p21, vascular dysfunction and remodeling. In vitro, we demonstrated that prolonged TMAO treatment induced senescence in human umbilical vein endothelial cells (HUVECs), characterized by reduced cell proliferation, increased expressions of senescence markers, stagnate G0/G1, and impaired cell migration. Furthermore, TMAO suppressed sirtuin 1 ([[SIRT1]]) expression and increased oxidative stress both in vivo and in vitro and then activated the p53/p21/Rb pathway resulting in increased p53, acetylation of p53, p21, and decreased [[CDK2]], cyclinE1, and phosphorylation of Rb. In summary, these data suggest that elevated circulating TMAO during the aging process may deteriorate EC senescence and vascular aging, which is probably associated with repression of [[SIRT1]] expression and increased oxidative stress, and, thus, the activation of the p53/p21/Rb pathway.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* Animals
* Blood Proteins
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* Disease Models, Animal
* Endothelium, Vascular
* Gastrointestinal Microbiome
* Human Umbilical Vein Endothelial Cells
* Humans
* Methylamines
* Mice
* Mice, Mutant Strains
* Oxidative Stress
* Signal Transduction
* Tumor Suppressor Protein p53
* Young Adult
* beta-Galactosidase
|keywords=* Endothelial cell senescence
* Oxidative stress
* SIRT1
* Trimethylamine-N-oxide (TMAO)
* Vascular aging
|full-text-url=https://sci-hub.do/10.1016/j.freeradbiomed.2018.01.007
}}
{{medline-entry
|title=Inhibition of [[CIP2A]] attenuates tumor progression by inducing cell cycle arrest and promoting cellular senescence in hepatocellular carcinoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29175329
|abstract=[[CIP2A]] is a recent identified oncogene that inhibits protein phosphatase 2A (PP2A) and stabilizes c-Myc in cancer cells. To investigate the potential oncogenic role and prognostic value of [[CIP2A]], we comprehensively analyzed the [[CIP2A]] expression levels in pan-cancer and observed high expression level of [[CIP2A]] in majority cancer types, including hepatocellular carcinoma (HCC). Based on a validation cohort including 60 HCC and 20 non-tumorous tissue samples, we further confirmed the high mRNA and protein expression levels of [[CIP2A]] in HCC, and found high [[CIP2A]] mRNA expression level was associated with unfavorable overall and recurrence-free survival in patients with HCC. Mechanistic investigations revealed that inhibition of [[CIP2A]] significantly attenuated cellular proliferation in vitro and tumourigenicity in vivo. Bioinformatic analysis suggested that [[CIP2A]] might be involved in regulating cell cycle. Our experimental data further confirmed [[CIP2A]] knockdown induced cell cycle arrest at G1 phase. We found accumulated cellular senescence in HCC cells with [[CIP2A]] knockdown, companying expression changes of senescence associated proteins (p21, [[CDK2]], [[CDK4]], cyclin D1, [[MCM7]] and FoxM1). Mechanistically, [[CIP2A]] knockdown repressed FoxM1 expression and induced FoxM1 dephosphorylation. Moreover, inhibition of PP2A by phosphatase inhibitor rescued the repression of FoxM1. Taken together, our results showed that [[CIP2A]] was highly expressed in HCC. Inhibition of [[CIP2A]] induced cell cycle arrest and promoted cellular senescence via repressing FoxM1 transcriptional activity, suggesting a potential anti-cancer target for patients with HCC.
|mesh-terms=* Autoantigens
* Biomarkers, Tumor
* Carcinoma, Hepatocellular
* Cell Cycle Checkpoints
* Cell Line, Tumor
* Cellular Senescence
* Disease Progression
* Forkhead Box Protein M1
* Gene Expression
* Gene Knockdown Techniques
* Hep G2 Cells
* Humans
* Intracellular Signaling Peptides and Proteins
* Liver Neoplasms
* Membrane Proteins
* Oncogenes
* Prognosis
* RNA, Messenger
* RNA, Neoplasm
|keywords=* CIP2A
* Cell cycle
* Cellular senescence
* FoxM1
* Hepatocellular carcinoma
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2017.11.124
}}
{{medline-entry
|title=G protein-coupled receptor kinase 4-induced cellular senescence and its senescence-associated gene expression profiling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28912086
|abstract=Senescent cells have lost their capacity for proliferation and manifest as irreversibly in cell cycle arrest. Many membrane receptors, including G protein-coupled receptors (GPCRs), initiate a variety of intracellular signaling cascades modulating cell division and potentially play roles in triggering cellular senescence response. GPCR kinases (GRKs) belong to a family of serine/threonine kinases. Although their role in homologous desensitization of activated GPCRs is well established, the involvement of the kinases in cell proliferation is still largely unknown. In this study, we isolated [[GRK4]]-GFP expressing HEK293 cells by fluorescence-activated cell sorting (FACS) and found that the ectopic expression of [[GRK4]] halted cell proliferation. Cells expressing [[GRK4]] ([[GRK4]]( )) demonstrated cell cycle G1/G0 phase arrest, accompanied with significant increase of senescence-associated-β-galactosidase (SA-β-Gal) activity. Expression profiling analysis of 78 senescence-related genes by qRT-PCR showed a total of 17 genes significantly changed in [[GRK4]]( ) cells (≥ 2 fold, p < 0.05). Among these, 9 genes - [[AKT1]], p16 , p27 , p19 , [[IGFBP3]], [[MAPK14]], [[PLAU]], [[THBS1]], [[TP73]] - were up-regulated, while 8 genes, Cyclin A2, Cyclin D1, [[CDK2]], [[CDK6]], [[ETS1]], [[NBN]], [[RB1]], [[SIRT1]], were down-regulated. The increase in cyclin-dependent kinase inhibitors (p16, p27) and p38 MAPK proteins ([[MAPK14]]) was validated by immunoblotting. Neither p53 nor p21  protein was detectable, suggesting no p53 activation in the HEK293 cells. These results unveil a novel function of [[GRK4]] on triggering a p53-independent cellular senescence, which involves an intricate signaling network.
|mesh-terms=* Cell Division
* Cell Line, Tumor
* Cell Proliferation
* Cellular Senescence
* Flow Cytometry
* G-Protein-Coupled Receptor Kinase 4
* Gene Expression Profiling
* Gene Expression Regulation
* HEK293 Cells
* Humans
* MCF-7 Cells
* Transcriptome
* Tumor Suppressor Protein p53
|keywords=* Cellular senescence
* G protein-coupled receptor kinase 4
* Gene expression profiling
* p53-independent senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944352
}}
{{medline-entry
|title=Pneumolysin induces cellular senescence by increasing ROS production and activation of MAPK/NF-κB signal pathway in glial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28232188
|abstract=Senescence is an irreversible proliferation arrest that is induced by various stress stimuli including genotoxin. Pneumolysin (PLY) is a pathogenicity factor unique to Streptococcus pneumoniae that is important in pneumococcal-induced diseases such as otitis media, meningitis and pneumonia. However, the cell fate response to the toxin is mechanistically unclear. We investigated the effect of PLY on cellular senescence in BV-2 microglial cells. Exposure to PLY resulted in changes in the expression of phospho-p53, p21, p16, pRb and [[CDK2]] and increased the number of senescence associated β-gal positive cells. PLY-treatment also increased PAI-1 expression and cell proliferation arrest in concentration- and time-dependent manners. PLY induced NF-κB activation and phosphorylation of SIRT-1, ERK1/2, JNK, and p38 MAPK. In addition, PLY increased the production of reactive oxygen species. Overall, the results suggest that PLY regulates microglial cellular senescence by enhancing production of reactive oxygen species, activation of MAPK and NF-κB, and phosphorylation of SIRT-1.
|mesh-terms=* Animals
* Bacterial Proteins
* Cell Line
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Humans
* MAP Kinase Signaling System
* Mice
* Mitogen-Activated Protein Kinases
* NF-kappa B
* Neuroglia
* Phosphorylation
* Rats
* Reactive Oxygen Species
* Signal Transduction
* Sirtuin 1
* Streptococcus pneumoniae
* Streptolysins
|keywords=* Cellular senescence
* Glial cells
* MAPK
* NF-κB
* Pneumolysin
* ROS
|full-text-url=https://sci-hub.do/10.1016/j.toxicon.2017.02.017
}}
{{medline-entry
|title=The protein-interaction network with functional roles in tumorigenesis, neurodegeneration, and aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27699588
|abstract=The present review summarizes the knowledge about a protein-interaction network, which includes proteins with significant functions in the mechanisms of aging and age-related diseases. All the detected interacting proteins TPPII, p53, [[MYBBP1A]], [[CDK2]] and [[SIRT7]], [[SIRT6]], and CD147 are suitable for the development of antitumor therapeutics and treatments for diseases of aging. TPPII and [[SIRT6]] directly affect glucose metabolism which drive malignant growth. In addition, [[SIRT6]] activators are attractive candidates for Alzheimer's disease (AD) due to the protection effect of [[SIRT6]] overexpression from DNA damage. TPPII activity exhibits a decreasing effect on mTOR signaling, and its requirement for the degradation of Aβ peptides in the human fibroblasts suggests that it has dual functions in tumorigenesis and AD-related pathology. Likewise, the direct promotion of the invasiveness of breast epithelial cells and the contribution to the Aβ degradation by stimulating the matrix metalloproteinases production suggest a double functional role for CD147. An association of the partial portion of cellular CD147 to γ-secretase further supports the functional relation to AD pathology. The animal and cellular models with downregulated or knockout TPPII, p53, [[SIRT6]], [[SIRT7]], and [[MYBBP1A]] expression levels illustrate similar functions of the interacting proteins. They demonstrate similar effects on the length of life span, premature aging, and lipid metabolism. The presented protein-interaction network is relevant to the discoveries of the mechanisms of tumorigenesis, aging, and neurodegeneration.
|mesh-terms=* Aging
* Alzheimer Disease
* Animals
* Cell Transformation, Neoplastic
* Humans
* Neoplasm Proteins
* Nerve Tissue Proteins
|keywords=* CD147
* MYBBP1A
* P53
* SIRT6
* SIRT7
* TPPII
|full-text-url=https://sci-hub.do/10.1007/s11010-016-2836-5
}}
{{medline-entry
|title=A steroid like phytochemical Antcin M is an anti-aging reagent that eliminates hyperglycemia-accelerated premature senescence in dermal fibroblasts by direct activation of Nrf2 and SIRT-1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27542238
|abstract=The present study revealed the anti-aging properties of antcin M (ANM) and elucidated the molecular mechanism underlying the effects. We found that exposure of human normal dermal fibroblasts (HNDFs) to high-glucose (HG, 30 mM) for 3 days, accelerated G0/G1 phase arrest and senescence. Indeed, co-treatment with ANM (10 µM) significantly attenuated HG-induced growth arrest and promoted cell proliferation. Further molecular analysis revealed that ANM blocked the HG-induced reduction in G1-S transition regulatory proteins such as cyclin D, cyclin E, [[CDK4]], [[CDK6]], [[CDK2]] and protein retinoblastoma (pRb). In addition, treatment with ANM eliminated HG-induced reactive oxygen species (ROS) through the induction of anti-oxidant genes, HO-1 and NQO-1 via transcriptional activation of Nrf2. Moreover, treatment with ANM abolished HG-induced SIPS as evidenced by reduced senescence-associated β-galactosidase (SA-β-gal) activity. This effect was further confirmed by reduction in senescence-associated marker proteins including, p21CIP1, p16INK4A, and p53/FoxO1 acetylation. Also, the HG-induced decline in aging-related marker protein SMP30 was rescued by ANM. Furthermore, treatment with ANM increased SIRT-1 expression, and prevented SIRT-1 depletion. This protection was consistent with inhibition of SIRT-1 phosphorylation at Ser47 followed by blocking its upstream kinases, p38 MAPK and JNK/SAPK. Further analysis revealed that ANM partially protected HG-induced senescence in SIRT-1 silenced cells. A similar effect was also observed in Nrf2 silenced cells. However, a complete loss of protection was observed in both Nrf2 and SIRT-1 knockdown cells suggesting that both induction of Nrf2-mediated anti-oxidant defense and SIRT-1-mediated deacetylation activity contribute to the anti-aging properties of ANM in vitro. Result of in vivo studies shows that ANM-treated C. elegens exhibits an increased survival rate during HG-induced oxidative stress insult. Furthermore, ANM significantly extended the life span of C. elegans. Taken together, our results suggest the potential application of ANM in age-related diseases or as a preventive reagent against aging process.
|mesh-terms=* Acetylcysteine
* Antioxidants
* Antrodia
* Apoptosis
* Cell Cycle
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Cholestenones
* Endothelial Cells
* Fibroblasts
* Gene Silencing
* Glucose
* Humans
* Hyperglycemia
* Medicine, Chinese Traditional
* NF-E2-Related Factor 2
* Oxidative Stress
* Phosphorylation
* Phytochemicals
* Reactive Oxygen Species
* Resveratrol
* Retinoblastoma Protein
* Sirtuin 1
* Skin
* Stilbenes
* Triterpenes
|keywords=* Antcin M
* Gerotarget
* SIRT-1
* antrodia salmonea
* hyperglycemia
* stress-induced premature senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325331
}}
{{medline-entry
|title=Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26987798
|abstract=Dysregulated repair of lung injury often results in lung fibrosis characterized by unremitting deposition of matrix components including glycosaminoglycan hyaluronan (HA). HA is mainly produced by hyaluronan synthases (HAS) in mesenchymal cells. We previously demonstrated that over-expression of [[HAS2]] in mesenchymal cells in mice regulates the invasiveness of fibroblasts and promotes severe lung fibrosis. The mechanisms that control the resolution of lung fibrosis are unknown. We propose that a critical step in resolving fibrosis is the induction of senescence in fibrotic fibroblasts and hyaluronan synthase 2 may regulate this process. We found that fibrotic fibroblasts developed the characteristics of replicative senescence in culture and that [[HAS2]] expression was dramatically down-regulated. Furthermore, down-regulation of [[HAS2]] initiated and regulated fibroblast senescence through a p27-[[CDK2]]-[[SKP2]] pathway. Deletion of [[HAS2]] in mouse mesenchymal cells increased the cellular senescence of fibroblasts in bleomycin-induced mouse lung fibrosis in vivo. These data suggest that [[HAS2]] may be a critical regulator of the fate of pulmonary fibrosis and we propose a model where over-expression of [[HAS2]] promotes an invasive phenotype resulting in severe fibrosis and down-regulation of [[HAS2]] promotes resolution. Targeting [[HAS2]] to induce fibroblast senescence could be an attractive approach to resolve tissue fibrosis.
|mesh-terms=* Animals
* Cells, Cultured
* Cellular Senescence
* Fibroblasts
* Humans
* Hyaluronan Synthases
* Mice, Transgenic
* Pulmonary Fibrosis
|keywords=* Cell cycle
* Fibrosis
* Fibrosis resolution
* Lung fibrosis
* Matrix
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383204
}}
{{medline-entry
|title=Double staining of β-galactosidase with fibrosis and cancer markers reveals the chronological appearance of senescence in liver carcinogenesis induced by diethylnitrosamine.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26589970
|abstract=Cellular senescence is characterized by irreversible cell arrest and is associated with the development of chronic diseases, including cancer. Here, we investigated the induction of cellular senescence during liver carcinogenesis. Liver cancer was induced in Fischer 344 rats with a weekly intraperitoneal injection of diethylnitrosamine (50mg/kg body weight) for 16 weeks. Double-detection of β-galactosidase with Ki67 for cell proliferation; a-SMA and Pdgfrb for cell specificity; p53, p21, p16, and cyclin D1, [[CDK2]], and [[CDK4]] for senescence-associated molecular pathways and γ-glutamyltranspeptidase (GGT) for hepatocarcinogenesis was assessed to determine the association of these markers with cellular senescence. DNA damage was measured through senescence-associated heterochromatin foci (SAHF) detection. Progressive cellular senescence was observed in both fibrotic septa and hepatocytes from week 10 to 18. The maximum peak of positive senescent and fibrotic cells was observed at week 16 and decreased at week 18, but cell proliferation remained high. Whereas the increased p16 expression and SAHF were concomitant with that of β-galactosidase, those of p53 and p21 were barely detected. Furthermore, β-galactosidase positive myofibroblast-like cells were mainly surrounding GGT-positive tumors. Our findings showed that in hepatocarcinogenesis by diethylnitrosamine, cellular senescence is associated with p16 pathway activation and is mainly localized in myofibroblast-like cells. 
|mesh-terms=* Animals
* Biomarkers, Tumor
* Carcinogenesis
* Carcinogens
* Cell Proliferation
* Cellular Senescence
* DNA Damage
* Diethylnitrosamine
* Fibrosis
* Ki-67 Antigen
* Liver Neoplasms
* Male
* Neoplasms
* Rats
* Rats, Inbred F344
* beta-Galactosidase
* gamma-Glutamyltransferase
|keywords=* Fibrosis
* Hepatocarcinogenesis
* N-Diethylnitrosamine
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.toxlet.2015.11.011
}}
{{medline-entry
|title=Proton irradiation impacts age-driven modulations of cancer progression influenced by immune system transcriptome modifications from splenic tissue.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26253138
|abstract=Age plays a crucial role in the interplay between tumor and host, with additional impact due to irradiation. Proton irradiation of tumors induces biological modulations including inhibition of angiogenic and immune factors critical to 'hallmark' processes impacting tumor development. Proton irradiation has also provided promising results for proton therapy in cancer due to targeting advantages. Additionally, protons may contribute to the carcinogenesis risk from space travel (due to the high proportion of high-energy protons in space radiation). Through a systems biology approach, we investigated how host tissue (i.e. splenic tissue) of tumor-bearing mice was altered with age, with or without whole-body proton exposure. Transcriptome analysis was performed on splenic tissue from adolescent (68-day) versus old (736-day) C57BL/6 male mice injected with Lewis lung carcinoma cells with or without three fractionations of 0.5 Gy (1-GeV) proton irradiation. Global transcriptome analysis indicated that proton irradiation of adolescent hosts caused significant signaling changes within splenic tissues that support carcinogenesis within the mice, as compared with older subjects. Increases in cell cycling and immunosuppression in irradiated adolescent hosts with [[CDK2]], [[MCM7]], [[CD74]] and [[RUVBL2]] indicated these were the key genes involved in the regulatory changes in the host environment response (i.e. the spleen). Collectively, these results suggest that a significant biological component of proton irradiation is modulated by host age through promotion of carcinogenesis in adolescence and resistance to immunosuppression, carcinogenesis and genetic perturbation associated with advancing age. 
|mesh-terms=* Age Factors
* Animals
* Carcinoma, Lewis Lung
* Cell Cycle
* Cell Line, Tumor
* Cell Proliferation
* Disease Models, Animal
* Disease Progression
* Humans
* Immune System
* Male
* Mice
* Mice, Inbred C57BL
* Neoplasm Transplantation
* Neoplasms
* Protons
* Radiation, Ionizing
* Spleen
* Transcriptome
|keywords=* aging and cancer
* bioinformatics
* immunosuppression
* protons
* spleen
* transcriptome analysis
* tumor microenvironment
* tumor progression
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577010
}}
{{medline-entry
|title=Cyclin-dependent kinase inhibitor p21(Waf1): contemporary view on its role in senescence and oncogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22817456
|abstract=p21(Waf1) was identified as a protein suppressing cyclin E/A-[[CDK2]] activity and was originally considered as a negative regulator of the cell cycle and a tumor suppressor. It is now considered that p21(Waf1) has alternative functions, and the view of its role in cellular processes has begun to change. At present, p21(Waf1) is known to be involved in regulation of fundamental cellular programs: cell proliferation, differentiation, migration, senescence, and apoptosis. In fact, it not only exhibits antioncogenic, but also oncogenic properties. This review provides a contemporary understanding of the functions of p21(Waf1) depending on its intracellular localization. On one hand, when in the nucleus, it serves as a negative cell cycle regulator and tumor suppressor, in particular by participating in the launch of a senescence program. On the other hand, when p21(Waf1) is localized in the cytoplasm, it acts as an oncogene by regulating migration, apoptosis, and proliferation.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Cell Cycle
* Cell Differentiation
* Cell Division
* Cell Nucleus
* Cell Physiological Phenomena
* Cell Transformation, Neoplastic
* Cellular Senescence
* Cyclin E
* Cyclin-Dependent Kinase 2
* Cyclin-Dependent Kinase Inhibitor p21
* Cytoplasm
* Humans

|full-text-url=https://sci-hub.do/10.1134/S000629791206003X
}}
{{medline-entry
|title=D-type cyclins and G1 progression during liver development in the rat.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/15809057
|abstract=Initiation and progression through G1 requires the activity of signaling complexes containing cyclins (D- or E-type) and cyclin-dependent kinases ([[CDK4]]/6 and [[CDK2]], respectively). We set out to identify the G1-phase cyclins and CDKs that are operative during late gestation liver development in the rat. This is a period during which hepatocytes show a high rate of proliferation that is, at least in part, independent of the mitogenic signaling pathways that are functional in mature hepatocytes. RNase protection assay and Western immunoblotting indicated that cyclin D1 is expressed at similar levels in fetal and adult liver. When cyclin D1 was induced after partial hepatectomy, its predominant CDK-binding partner was [[CDK4]]. In contrast, cyclins D2 and D3 predominated in fetal liver and were complexed with both [[CDK4]] and [[CDK6]]. Little [[CDK6]] protein was expressed in quiescent or regenerating adult liver. Cyclins E1 and E2 were both transcriptionally up-regulated in fetal liver. Activity of complexes containing cyclins E1 and E2 was higher in fetal liver, as was content of the cell cycle regulator, Rb. In fetal liver, Rb was highly phosphorylated at both cyclin D- and cyclin E-dependent sites. In conclusion, liver development is associated with a switch from cyclin D2/D3-containing complexes to cyclin D1:[[CDK4]] complexes. We speculate that the switch in D-type cyclins may be associated with the dependence on mitogenic signaling that develops as hepatocytes mature.
|mesh-terms=* Aging
* Animals
* Antibodies
* Cyclin D1
* Cyclin D2
* Cyclin D3
* Cyclin E
* Cyclin-Dependent Kinases
* Cyclins
* Female
* G1 Phase
* Gene Expression Regulation, Developmental
* Immunoprecipitation
* Liver
* Liver Regeneration
* Male
* Phosphorylation
* Pregnancy
* Protein Binding
* RNA, Messenger
* Rats

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

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

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

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