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

• Published in: Molecular cancer research Vol. 3; no. 11; pp. 627 - 634
• Main Authors: Aliouat-Denis, Cécile-Marie, Dendouga, Najoua, Van den Wyngaert, Ilse, Goehlmann, Hinrich, Steller, Ulf, van de Weyer, Inez, Van Slycken, Nele, Andries, Luc, Kass, Stefan, Luyten, Walter, Janicot, Michel, Vialard, Jorge E
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.11.2005
• Subjects: Apoptosis - physiology; Breast Neoplasms; Cell Division - physiology; Cell Line, Transformed; Cell Line, Tumor; Cellular Senescence - physiology; checkpoint; Checkpoint Kinase 2; Chk2; Cyclin-Dependent Kinase Inhibitor p21 - genetics; DNA damage; Gene Expression Regulation, Neoplastic; Humans; Keratinocytes - cytology; Lung Neoplasms; p21; p53; Protein-Serine-Threonine Kinases - genetics; Retroviridae - genetics; RNA, Small Interfering; senescence; Transduction, Genetic; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-05-0121

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.