p53-independent regulation of p21Waf1/Cip1 expression and senescence by Chk2

Mol Cancer Res. 2005 Nov;3(11):627-34. doi: 10.1158/1541-7786.MCR-05-0121.

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 p21(Waf1/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.

MeSH terms

  • Apoptosis / physiology
  • Breast Neoplasms
  • Cell Division / physiology
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cellular Senescence / physiology
  • Checkpoint Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Keratinocytes / cytology
  • Lung Neoplasms
  • Protein-Serine-Threonine Kinases / genetics*
  • RNA, Small Interfering
  • Retroviridae / genetics
  • Transduction, Genetic
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases