title: The Chk2 tumor suppressor is not required for p53 responses in human cancer cells.
abstract: Ionizing radiation damages chromosomal DNA and activates p53-dependent transcription in mammalian cells. The Chk2 protein kinase has been hypothesized to be the primary mediator of this response. We have rigorously tested this hypothesis in human cells by disrupting the CHK2 gene through homologous recombination. We found that the p53 response was unexpectedly robust in such cells. Phosphorylation of p53 at serine 20, accumulation of p53 protein, transcriptional activation of p53 target genes, and cell cycle arrest and apoptotic death phenotypes were completely intact regardless of CHK2 status. Our results indicate that Chk2 kinase is not required for p53 activation in human cells and explain why CHK2 and TP53 mutations can jointly occur in human tumors.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University, Baltimore, Maryland 21231, USA. bunzfre@mail.jhmi.edu
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Jallepalli
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Fred
authors.initials: F
authors.lastname: Bunz
mesh_terms: D064447:Checkpoint Kinase 2; D003110:Colonic Neoplasms; D004249:DNA Damage / Q000502:physiology; D005091:Exons; D016195:G2 Phase / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases