BRCA1 Is Phosphorylated at Serine 1497 In Vivo at a Cyclin-Dependent Kinase 2 Phosphorylation Site

Ruffner, Heinz; Jiang, Wei; Craig, Anne; Hunter, Tony; Verma, Inder M.

doi:10.1128/mcb.19.7.4843

Cited by 105 publications

(88 citation statements)

References 72 publications

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“…Our data demonstrates that the principal areas of interaction are the N terminus (aa 1-500) and aa 504-802. Furthermore, BRCA1 is targeted for phosphorylation by numerous cell-cycle kinases including cyclin A/cdk2, cyclin E/cdk2 and cyclin D1/cdk4 (Chen et al, 1996;Ruffner et al, 1999). BRCA1, through its tumor suppressor function, acts to protect cells from unwanted excessive growth.…”

Section: Discussionmentioning

confidence: 99%

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Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells

et al. 2007

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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.

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Section: Discussionmentioning

confidence: 99%

“…Likewise, various cyclin/cdk complexes, including cyclin D, have been shown to phosphorylate BRCA1 (Wang et al, 1997;Ruffner et al, 1999); however, the consequence of cyclin D1/cdk phosphorylation on BRCA1 has not been determined.…”

Section: Introductionmentioning

confidence: 99%

Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells

et al. 2007

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“…Immunoprecipitation/ in vitro kinase assays revealed that several cyclins and associated cyclin-dependent kinases (cyclins D and A, CDK2) can associate with and phosphorylate BRCA1 on tyrosine residues in human mammary cell line HBL100 (Wang et al, 1997). In addition, a CDK2/cyclin A or E complex phosphorylates BRCA1 at a CDK consensus phosphorylation site (serine-1497) both in vitro and in vivo (Ruffner et al, 1999).…”

Section: Regulation Of Brca1 Expressionmentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

241

195

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The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast cancer and breast-ovarian cancer syndromes in women. While inherited mutations of BRCA1 are responsible for about 40-45% of hereditary breast cancers, these mutations account for only 2-3% of all breast cancers, since the BRCA1 gene is rarely mutated in sporadic breast cancers. However, BRCA1 expression is frequently reduced or absent in sporadic cancers, suggesting a much wider role in mammary carcinogenesis. Since BRCA1 was cloned in 1994, its molecular function has been the subject of intense investigation. These studies have revealed multiple functions of the BRCA1 that may contribute to its tumor suppressor activity, including roles in: cell cycle progression, several highly specialized DNA repair processes, DNA damage-responsive cell cycle checkpoints, regulation of a set of specific transcriptional pathways, and apoptosis. Many of these functions are linked to protein:protein interactions involving different portions of the 1,863 amino acid (aa) BRCA1 protein. BRCA1 functions in cell cycle progression and the DNA damage response appear to be regulated by distinct and specific phosphorylation events, but the molecular pathways activated by these phosphorylations are only beginning to be unraveled. In addition, the reason that BRCA1 mutation carriers develop specific tumor types (breast and ovarian cancers in women and possibly prostate cancers in men) is not clearly understood. Elucidation of the precise molecular functions of the BRCA1 gene product will greatly enhance our understanding of the pathogenesis of hereditary as well as sporadic mammary carcinogenesis.

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“…Cyclin E, an essential cyclin that is expressed in late G1 and early S phase, regulates the phosphorylation of many proteins that are important for cell proliferation, including the retinoblastoma protein (RB), 1 BRCA1, 2 and NPAT. 3 Cyclin E is overexpressed in approximately a quarter of all breast tumors 4 and studies have found that cyclin E overexpression and an increase in cyclin E/ CDK2 kinase activity correlates with a poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

Cyclin E overexpression enhances cytokine-mediated apoptosis in MCF7 breast cancer cells

Dhillon

Mudryj

2003

Genes Immun

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Cyclin E, the regulatory component of the cyclin E/cyclin-dependent kinase (CDK) complex, is required for proliferation and overexpression of this cyclin is associated with many types of human tumors. To elucidate the mechanism by which cyclin E overexpression promotes tumorigenesis, cyclin E was overexpressed in two breast cancer lines: MCF7 and T47D. Cells overexpressing cyclin E display a marked decrease in the expression of Bcl-2, an antiapoptotic protein, and increased levels of the proapoptotic proteins Bad and Bax. The levels of Bcl-X L and Mcl-1 remain unchanged. Since the homeostasis of pro-and antiapoptotic proteins was altered, we asked if cyclin E overexpression modifies responses to cytokines. MCF7 cyclin E overexpressing cells have an enhanced sensitivity to Fas, TRAIL, and TNF-a-induced apoptosis. T47D cells overexpressing cyclin E have a significant increase in TNF-a and TRAIL-induced apoptosis. In conclusion, our results provide a link between expression of cyclin E, deregulation of Bcl-2, and an altered response to cytokine-mediated apoptosis.

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BRCA1 Is Phosphorylated at Serine 1497 In Vivo at a Cyclin-Dependent Kinase 2 Phosphorylation Site

Cited by 105 publications

References 72 publications

Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells

Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells

BRCA1 gene in breast cancer

Cyclin E overexpression enhances cytokine-mediated apoptosis in MCF7 breast cancer cells

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