Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells.
The inheritance of one defective BRCA1 or BRCA2 allele predisposes an individual to developing breast and ovarian cancers. BRCA1 is a multifunctional tumor suppressor protein, which through interaction with a vast array of proteins has implications in processes such as cell cycle, transcription, DNA damage response and chromatin remodeling. Conversely, the oncogene, cyclin D1 is overexpressed in about 35% of all breast cancer cases. In this study, we provide detailed analyses on the phosphorylation state of BRCA1 by cyclin D1/cdk4 complexes. In particular, we have identified Ser 632 of BRCA1 as a cyclin D1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin D1/cdk4 activity resulted in increased BRCA1 DNA binding at particular promoters in vivo. In addition, we identified multiple novel genes that are bound by BRCA1 in vivo. Collectively, these results indicate that cyclin D1/cdk4-mediated phosphorylation of BRCA1 inhibits the ability of BRCA1 to be recruited to particular promoters in vivo. Therefore, cyclin D1/Cdk4 phosphorylation of BRCA1 could provide a mechanism to interfere with the DNA-dependent activities of BRCA1.
Kehn
K
K
Department of Biochemistry and Molecular Biology, The George Washington University, Washington, DC 20037, USA.
Berro
R
R
Alhaj
A
A
Bottazzi
M E
ME
Yeh
W-I
WI
Klase
Z
Z
Van Duyne
R
R
Fu
S
S
Kashanchi
F
F
D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000032:analysis / Q000378:metabolism*; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019938:Cyclin D1 / Q000032:analysis / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016192:Resting Phase, Cell Cycle
D019313:BRCA1 Protein; D019938:Cyclin D1; D004247:DNA; D051358:Cyclin-Dependent Kinase 4