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

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.

[1]  H. A. Rogoff,et al.  Dual induction of apoptosis and senescence in cancer cells by Chk2 activation: checkpoint activation as a strategy against cancer. , 2005, Cancer research.

[2]  Jiri Bartek,et al.  Cell-cycle checkpoints and cancer , 2004, Nature.

[3]  C. Prives,et al.  The Chk2 protein kinase. , 2004, DNA repair.

[4]  D. Meek,et al.  The p53 response to DNA damage. , 2004, DNA repair.

[5]  V. Dulic,et al.  DNA damage checkpoint kinase Chk2 triggers replicative senescence , 2004, The EMBO journal.

[6]  J. Shay,et al.  Hallmarks of senescence in carcinogenesis and cancer therapy , 2004, Oncogene.

[7]  B. Dörken,et al.  Cellular senescence in cancer treatment: friend or foe? , 2004, The Journal of clinical investigation.

[8]  S. Lowe,et al.  Control of apoptosis by p53 , 2003, Oncogene.

[9]  N. Carter,et al.  A DNA damage checkpoint response in telomere-initiated senescence , 2003, Nature.

[10]  Wafik S El-Deiry,et al.  P53 and radiation responses , 2003, Oncogene.

[11]  I. Roninson,et al.  Tumor cell senescence in cancer treatment. , 2003, Cancer research.

[12]  H. Piwnica-Worms,et al.  Regulation of the Chk2 protein kinase by oligomerization-mediated cis- and trans-phosphorylation. , 2003, Molecular cancer research : MCR.

[13]  Jiri Bartek,et al.  Chk1 and Chk2 kinases in checkpoint control and cancer. , 2003, Cancer cell.

[14]  C. Schmitt.  Senescence, apoptosis and therapy — cutting the lifelines of cancer , 2003, Nature Reviews Cancer.

[15]  Y. Shiloh.  ATM and related protein kinases: safeguarding genome integrity , 2003, Nature Reviews Cancer.

[16]  M. Janicot,et al.  Inhibition of Histone Deacetylases by Chlamydocin Induces Apoptosis and Proteasome-Mediated Degradation of Survivin , 2003, Journal of Pharmacology and Experimental Therapeutics.

[17]  W. Woods,et al.  DNA Damage Induces a Novel p53-Survivin Signaling Pathway Regulating Cell Cycle and Apoptosis in Acute Lymphoblastic Leukemia Cells , 2002, Journal of Pharmacology and Experimental Therapeutics.

[18]  D. Stern,et al.  Chk2 Activation and Phosphorylation-Dependent Oligomerization , 2002, Molecular and Cellular Biology.

[19]  I. Roninson.  Oncogenic functions of tumour suppressor p21(Waf1/Cip1/Sdi1): association with cell senescence and tumour-promoting activities of stromal fibroblasts. , 2002, Cancer letters.

[20]  Soyoung Lee,et al.  A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy , 2002, Cell.

[21]  W. R. Bishop,et al.  Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway , 2002, Oncogene.

[22]  S. Joel,et al.  DNA damage is able to induce senescence in tumor cells in vitro and in vivo. , 2002, Cancer research.

[23]  Jiandong Chen,et al.  Transcriptional Repression of the Anti-apoptoticsurvivin Gene by Wild Type p53* , 2002, The Journal of Biological Chemistry.

[24]  J. Bartek,et al.  Chk2 kinase — a busy messenger , 2001, Nature Reviews Molecular Cell Biology.

[25]  N. Mailand,et al.  DNA damage-activated kinase Chk2 is independent of proliferation or differentiation yet correlates with tissue biology. , 2001, Cancer research.

[26]  M. Broggini,et al.  DNA Damage Induces p53-dependent Down-regulation of hCHK1* , 2001, The Journal of Biological Chemistry.

[27]  Vanesa Gottifredi,et al.  p53 Down-Regulates CHK1 through p21 and the Retinoblastoma Protein , 2001, Molecular and Cellular Biology.

[28]  H. Piwnica-Worms,et al.  Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation. , 2000, Cancer research.

[29]  G. Nolan,et al.  Retroviral delivery of peptide modulators of cellular functions. , 2000, Molecular therapy : the journal of the American Society of Gene Therapy.

[30]  S. Elledge,et al.  DNA damage-induced activation of p53 by the checkpoint kinase Chk2. , 2000, Science.

[31]  Y Taya,et al.  The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. , 2000, Genes & development.

[32]  M. Nakanishi,et al.  Role of Human Cds1 (Chk2) Kinase in DNA Damage Checkpoint and Its Regulation by p53* , 1999, The Journal of Biological Chemistry.

[33]  A. Gartel,et al.  Transcriptional regulation of the p21((WAF1/CIP1)) gene. , 1999, Experimental cell research.

[34]  S. Elledge,et al.  Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. , 1998, Science.

[35]  G. D. De Meyer,et al.  RNA synthesis and splicing interferes with DNA in situ end labeling techniques used to detect apoptosis. , 1998, The American journal of pathology.

[36]  Å. Borg,et al.  Activated cell cycle checkpoints in epirubicin-treated breast cancer cells studied by BrdUrd-flow cytometry. , 1997, Cytometry.

[37]  C Roskelley,et al.  A biomarker that identifies senescent human cells in culture and in aging skin in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Xiao-Fan Wang,et al.  Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[39]  E. Coligan.  Current protocols in immunology , 1991 .

[40]  W. Allsbrook,et al.  Flow cytometric DNA analysis. , 1990, Clinical laboratory science : journal of the American Society for Medical Technology.

[41]  V. Ll.  Flow cytometric DNA analysis. , 1985 .