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 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.
Aliouat-Denis
Cécile-Marie
CM
Oncology Discovery Research and Early Development, Johnson & Johnson Pharmaceutical Research and Early Development, Beerse, Belgium.
Dendouga
Najoua
N
Van den Wyngaert
Ilse
I
Goehlmann
Hinrich
H
Steller
Ulf
U
van de Weyer
Inez
I
Van Slycken
Nele
N
Andries
Luc
L
Kass
Stefan
S
Luyten
Walter
W
Janicot
Michel
M
Vialard
Jorge E
JE
D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology; D064447:Checkpoint Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D008175:Lung Neoplasms; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034741:RNA, Small Interfering; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases