title: p53-independent regulation of p21Waf1/Cip1 expression and senescence by Chk2.
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.
authors.affiliation: Oncology Discovery Research and Early Development, Johnson & Johnson Pharmaceutical Research and Early Development, Beerse, Belgium.
authors.forename: Cécile-Marie
authors.initials: CM
authors.lastname: Aliouat-Denis
authors.forename: Najoua
authors.initials: N
authors.lastname: Dendouga
authors.forename: Ilse
authors.initials: I
authors.lastname: Van den Wyngaert
authors.forename: Hinrich
authors.initials: H
authors.lastname: Goehlmann
authors.forename: Ulf
authors.initials: U
authors.lastname: Steller
authors.forename: Inez
authors.initials: I
authors.lastname: van de Weyer
authors.forename: Nele
authors.initials: N
authors.lastname: Van Slycken
authors.forename: Luc
authors.initials: L
authors.lastname: Andries
authors.forename: Stefan
authors.initials: S
authors.lastname: Kass
authors.forename: Walter
authors.initials: W
authors.lastname: Luyten
authors.forename: Michel
authors.initials: M
authors.lastname: Janicot
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Vialard
mesh_terms: 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*
chemical_list: 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