p53-Independent Regulation of p21Waf1/Cip1 Expression and Senescence by Chk2

Abstract

The Chk2 kinase is a tumor suppressor and key component of the DNA damage checkpoint response that encompasses cell cycle arrest, apoptosis, and DNA repair. It has also been shown to have a role in replicative senescence resulting from dysfunctional telomeres. Some of these functions are at least partially exerted through activation of the p53 transcription factor. High-level expression of virally transduced Chk2 in A549 human lung carcinoma cells led to arrested proliferation, apoptosis, and senescence. These were accompanied by various molecular events, including p21Waf1/Cip1 (p21) transcriptional induction, consistent with p53 activation. However, Chk2-dependent senescence and p21 transcriptional induction also occurred in p53-defective SK-BR-3 (breast carcinoma) and HaCaT (immortalized keratinocyte) cells. Small interfering RNA -mediated knockdown of p21 in p53-defective cells expressing Chk2 resulted in a decrease in senescent cells. These results revealed a p53-independent role for Chk2 in p21 induction and senescence that may contribute to tumor suppression and genotoxic treatment outcome. (Mol Cancer Res 2005;3(11):627 -34)

Temporally distinct roles of ATM and ROS in genotoxic-stress-dependent induction and maintenance of cellular senescence

“…Results are mean6s.e.m. known as CDKN2A) proteins alone (Aliouat-Denis et al, 2005;Ben-Porath and Weinberg, 2005). Similar to p53, ROS has also been projected as a crucial molecule that regulates and maintains senescence, as it can damage DNA, proteins and lipids to induce the stress response, which in turn can affect the senescence phenotype (Colavitti and Finkel, 2005;Lu and Finkel, 2008;Macip et al, 2002).…”

“…This assumption is also supported through a number of models used for inducing cellular senescence in cultured cells. The models include: replicative exhaustion of primary mortal cell lines, which causes replicative senescence (Aliouat-Denis et al, 2005;Hayflick, 1965); exposure of cells to genotoxic stress such as c rays, H 2 O 2 etc, causing stress-induced senescence (Chen and Ames, 1994;Duan et al, 2005); and by hyperactivating oncogenes in cells, which causes oncogeneinduced senescence (Serrano et al, 1997). Whereas genotoxic stress leads to direct DNA damage, in oncogene activation and replicative exhaustion the DNA damage occurs through accumulation of errors during DNA replication and telomere shortening during every cell division (Chen et al, 2007;Di Micco et al, 2006;Maicher et al, 2012).…”

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

“…According to several studies, upregulation of p21 transcription can be through p53‐dependent pathways or p53‐independent pathways 49, 50, 51, 52. The promoter of p21 contains two conserved p53‐binding sites required for p53 responsiveness after DNA damage 53.…”

IGFBP-rP1 induces p21 expression through a p53-independent pathway, leading to cellular senescence of MCF-7 breast cancer cells

“…Secondly, IGFBP-rP1-induced p21 production was not alterated following p53 knockdown. Indeed, p21 has many roles in cell cycle control beyond its function as an effector of p53 responses to genotoxic stress (Aliouat-Denis et al 2005;Michieli et al 1994). p21 can also respond to extracellular signals such as TGF-b for cell cycle arrest (Datto et al 1995).…”