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Cell Cycle, Cell Death, and Senescence

p53-Independent Regulation of p21^Waf1/Cip1 Expression and Senescence by Chk2

¹ Oncology Discovery Research and Early Development, ² Advanced BioTechnologies, and ³ Genomic Technologies, Johnson & Johnson Pharmaceutical Research and Early Development, Beerse, Belgium and ⁴ Histogenex, Edegem, Belgium

Requests for reprints: Jorge E. Vialard, Oncology Discovery Research and Early Development, Johnson & Johnson Pharmaceutical Research and Early Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. Phone: 32-14-60-3971; Fax: 32-14-60-5403. E-mail: jvialard{at}prdbe.jnj.com

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.

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