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- W874049513 abstract "Proc Amer Assoc Cancer Res, Volume 45, 20041300 Germline mutations in the breast and ovarian tumor suppressor gene, BRCA1 , predispose women to breast and ovarian cancers. The gene product, BRCA1, is a protein of 1863 amino acids with two conserved domains. The BRCT domain at the carboxyl terminus is a motif found in many proteins involved in DNA repair and maintenance of genomic stability. The RING domain at the amino terminus is found in proteins involved in ubiquitylation. In response to DNA damage, BRCA1 becomes hyperphosphorylated and relocalizes to sites of DNA double strand breaks. We and others demonstrated that BRCA1 is involved in relaying the DNA damage signal. We established that in response to ionizing radiation (IR) BRCA1 activates the G2/M cell cycle checkpoint by regulating the expression, activity and cellular localization of key cell cycle proteins. Wild type full length BRCA1 expression in HCC1937 breast cancer cells, deficient for BRCA1, resulted in down regulation of cyclin B and Cdc25C while an increase in Wee1 and 14-3-3 proteins. Studies demonstrated that cancer predisposing mutations in the RING domain of BRCA1 prevent the activation of the G2/M checkpoint in response to DNA damage. Here we report that BRCA1 regulates the expression of checkpoint proteins via the proteosome. BRCA1 deficient and proficient breast cancer cells were treated with the proteosome inhibitors: calpain inhibitor (AL’L’N) and MG132 . we observed significant increase in the protein levels of Cdc25 and cyclin B in BRCA1 proficient cells treated with 5 μM of ALLN. Furthermore, ex-vivo ubiquitylation assays suggested that BRCA1 may tag cell cycle proteins with ubiquitin. We are currently investigating the role of BRCA1 in proteosome-mediated degradation of cell cycle proteins following DNA damage." @default.
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- W874049513 date "2004-04-01" @default.
- W874049513 modified "2023-09-23" @default.
- W874049513 title "BRCA1 regulates the expression of cell cycle proteins via the proteosome" @default.
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