Cellular Senescence and the Cell Cycle

Early multicellular organisms must gain adaptations to outcompete their unicellular ancestors, as well as other multicellular lineages. The tempo and mode of multicellular adaptation is influenced by many factors including the traits of individual cells. We consider how a fundamental aspect of cells, whether they reproduce via binary fission or budding, can affect the rate of adaptation in primitive multicellularity. We use mathematical models to study the spread of beneficial, growth rate mutations in unicellular populations and populations of multicellular filaments reproducing via binary fission or budding. Comparing populations once they reach carrying capacity, we find that the spread of mutations in multicellular budding populations is qualitatively distinct from the other populations and in general slower. Since budding and binary fission distribute age-accumulated damage differently, we consider the effects of cellular senescence. When growth rate decreases with cell age, we find that beneficial mutations can spread significantly faster in a multicellular budding population than its corresponding unicellular population or a population reproducing via binary fission. Our results demonstrate that basic aspects of the cell cycle can give rise to different rates of adaptation in multicellular organisms.

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Cellular Senescence in Liver Disease and Regeneration

Seminars in Liver Disease ◽

10.1055/s-0040-1722262 ◽

2021 ◽

Author(s):

Sofia Ferreira-Gonzalez ◽

Daniel Rodrigo-Torres ◽

Victoria L. Gadd ◽

Stuart J. Forbes

Keyword(s):

Cell Cycle ◽

Liver Disease ◽

Cell Cycle Arrest ◽

Genomic Instability ◽

Cellular Senescence ◽

Cell Populations ◽

Cycle Arrest ◽

Relevant Role ◽

Extent Of Damage

AbstractCellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.

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Inhibition of CIP2A attenuates tumor progression by inducing cell cycle arrest and promoting cellular senescence in hepatocellular carcinoma

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2017.11.124 ◽

2018 ◽

Vol 495 (2) ◽

pp. 1807-1814 ◽

Cited By ~ 5

Author(s):

Xue Yang ◽

Kai Qu ◽

Jie Tao ◽

Guozhi Yin ◽

Shaoshan Han ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Tumor Progression ◽

Cell Cycle Arrest ◽

Cellular Senescence ◽

Cycle Arrest

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Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts

PLoS ONE ◽

10.1371/journal.pone.0042150 ◽

2012 ◽

Vol 7 (8) ◽

pp. e42150 ◽

Cited By ~ 18

Author(s):

Sascha Schäuble ◽

Karolin Klement ◽

Shiva Marthandan ◽

Sandra Münch ◽

Ines Heiland ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cellular Senescence ◽

Human Fibroblasts ◽

Quantitative Model ◽

Cycle Arrest

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Heat shock protein 27 promotes cell cycle progression by down-regulating E2F transcription factor 4 and retinoblastoma family protein p130

Journal of Biological Chemistry ◽

10.1074/jbc.ra118.003310 ◽

2018 ◽

Vol 293 (41) ◽

pp. 15815-15826 ◽

Cited By ~ 5

Author(s):

Ah-Mee Park ◽

Ikuo Tsunoda ◽

Osamu Yoshie

Keyword(s):

Cell Cycle ◽

Heat Shock ◽

Heat Shock Protein ◽

Cellular Senescence ◽

Cell Cycle Progression ◽

Heat Shock Protein 27 ◽

Serum Starvation ◽

Cell Cycle Gene ◽

Cycle Progression ◽

Human Lung Fibroblast

Heat shock protein 27 (HSP27) protects cells under stress. Here, we demonstrate that HSP27 also promotes cell cycle progression of MRC-5 human lung fibroblast cells. Serum starvation for 24 h induced G1 arrest in these cells, and upon serum refeeding, the cells initiated cell cycle progression accompanied by an increase in HSP27 protein levels. HSP27 levels peaked at 12 h, and transcriptional up-regulation of six G2/M-related genes (CCNA2, CCNB1, CCNB2, CDC25C, CDCA3, and CDK1) peaked at 24–48 h. siRNA-mediated HSP27 silencing in proliferating MRC-5 cells induced G2 arrest coinciding with down-regulation of these six genes. Of note, the promoters of all of these genes have the cell cycle–dependent element and/or the cell cycle gene-homology region. These promoter regions are known to be bound by the E2F family proteins (E2F-1 to E2F-8) and retinoblastoma (RB) family proteins (RB1, p107, and p130), among which E2F-4 and p130 were strongly up-regulated in HSP27-knockdown cells. E2F-4 or p130 knockdown concomitant with the HSP27 knockdown rescued MRC-5 cells from G2 arrest and up-regulated the six cell cycle genes. Moreover, we observed cellular senescence in MRC-5 cells on day 3 after the HSP27 knockdown, as evidenced by increased senescence-associated β-gal activity and up-regulated inflammatory cytokines. The cellular senescence was also suppressed by the concomitant knockdown of E2F-4/HSP27 or p130/HSP27. Our findings indicate that HSP27 promotes cell cycle progression of MRC-5 cells by suppressing expression of the transcriptional repressors E2F-4 and p130.

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Dynamic transcriptome profiling in DNA damage-induced cellular senescence and transient cell-cycle arrest

Genomics ◽

10.1016/j.ygeno.2019.07.020 ◽

2020 ◽

Vol 112 (2) ◽

pp. 1309-1317 ◽

Cited By ~ 1

Author(s):

Zhen Zhao ◽

Qiongye Dong ◽

Xuehui Liu ◽

Lei Wei ◽

Liyang Liu ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Cellular Senescence ◽

Transcriptome Profiling ◽

Cycle Arrest

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Babam2 Regulates Cell Cycle Progression and Pluripotency in Mouse Embryonic Stem Cells as Revealed by Induced DNA Damage

Biomedicines ◽

10.3390/biomedicines8100397 ◽

2020 ◽

Vol 8 (10) ◽

pp. 397

Author(s):

Cheuk Yiu Tenny Chung ◽

Paulisally Hau Yi Lo ◽

Kenneth Ka Ho Lee

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Dna Damage ◽

Gamma Irradiation ◽

Cellular Senescence ◽

Cell Cycle Regulation ◽

Cell Cycle Progression ◽

Embryonic Stem ◽

Cycle Progression ◽

Cycle Regulation

BRISC and BRCA1-A complex member 2 (Babam2) plays an essential role in promoting cell cycle progression and preventing cellular senescence. Babam2-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 Babam2 in ESCs would enable us to understand the mechanism of Babam2 in cellular aging, cell cycle regulation, and pluripotency in ESCs. For this study, we generated Babam2 knockout (Babam2−/−) mESCs to investigate the function of Babam2 in mESCs. We demonstrated that the loss of Babam2 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 Babam2−/− mESCs following gamma irradiation. In addition, Babam2−/− 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 Babam2−/− mESCs. In summary, Babam2 maintains cell cycle regulation and pluripotency in mESCs in response to induced DNA damage.

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Oncogenic ras and p53 Cooperate To Induce Cellular Senescence

Molecular and Cellular Biology ◽

10.1128/mcb.22.10.3497-3508.2002 ◽

2002 ◽

Vol 22 (10) ◽

pp. 3497-3508 ◽

Cited By ~ 188

Author(s):

Gerardo Ferbeyre ◽

Elisa de Stanchina ◽

Athena W. Lin ◽

Emmanuelle Querido ◽

Mila E. McCurrach ◽

...

Keyword(s):

Cell Cycle ◽

Map Kinase ◽

Cell Cycle Arrest ◽

Cellular Senescence ◽

Null Mouse ◽

P53 Expression ◽

Oncogenic Ras ◽

Cycle Arrest ◽

Murine Fibroblasts ◽

Mitogen Activated Protein

ABSTRACT Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53val135 ) into p53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing p53, oncogenic Ras, or both gene products. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence. p19ARF was required for this effect, since p53 −/− ARF −/− double-null cells were unable to undergo senescence following coexpression of oncogenic Ras and p53. Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19ARF on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence. Hence, enforced p53 expression without oncogenic ras in p53 −/− mdm2 −/− double-null cells produced extremely high p53 levels but did not induce senescence. Taken together, our results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts p53 into a senescence inducer through both quantitative and qualitative mechanisms.

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