title: Collaboration of Brca1 and Chk2 in tumorigenesis.
abstract: Disruption of Brca1 results in cellular demise or tumorigenesis depending on cellular context. Inactivation of p53 contributes to Brca1-associated tumor susceptibility. However the activation of p53-dependent checkpoint/apoptotic signaling in the absence of Brca1 is poorly understood. Here, we show that Chk2 inactivation is partially equivalent to p53 inactivation, in that Chk2 deficiency facilitates the development, survival, and proliferation of Brca1-deficient T cells at the expense of genomic integrity. Brca1 deficiency was found to result in Chk2 phosphorylation and the Chk2-dependent accumulation and activation of p53. Furthermore, inactivation of Chk2 and Brca1 was cooperative in breast cancer. Our findings identify a critical role for Chk2 as a component of the DNA damage-signaling pathway activated in response to Brca1 deficiency.
authors.affiliation: Advanced Medical Discovery Institute, Ontario Cancer Institute, Toronto, Ontario M5G 2C1, Canada.
authors.forename: John Peter
authors.initials: JP
authors.lastname: McPherson
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Lemmers
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Anne
authors.initials: A
authors.lastname: Hakem
authors.forename: Jacinth
authors.initials: J
authors.lastname: Abraham
authors.forename: Eva
authors.initials: E
authors.lastname: Migon
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Matysiak-Zablocki
authors.forename: Laura
authors.initials: L
authors.lastname: Tamblyn
authors.forename: Otto
authors.initials: O
authors.lastname: Sanchez-Sweatman
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
authors.forename: Jeremy
authors.initials: J
authors.lastname: Squire
authors.forename: M Prakash
authors.initials: MP
authors.lastname: Hande
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
mesh_terms: D000818:Animals; D064447:Checkpoint Kinase 2; D002869:Chromosome Aberrations; D003043:Cocarcinogenesis; D005260:Female; D019398:Genes, BRCA1; D016158:Genes, p53; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000528:radiation effects
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases