Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Oncogene volume 26, pages 5060–5069 (2007)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Aubry C, Jenkins PR, Mahale S, Chaudhuri B, Marechal JD, Sutcliffe MJ . (2004). New fascaplysin-based CDK4-specific inhibitors: design, synthesis and biological activity. Chem Commun 15: 1696–1697.

    Article  Google Scholar 

  • Boulton SJ . (2006). Cellular functions of the BRCA tumour-suppressor proteins. Biochem Soc Trans 34: 633–645.

    Article  CAS  Google Scholar 

  • Cable PL, Wilson CA, Calzone FJ, Rauscher III FJ, Scully R, Livingston DM et al. (2003). Novel consensus DNA-binding sequence for BRCA1 protein complexes. Mol Carcinog 38: 85–96.

    Article  CAS  Google Scholar 

  • Chen Y, Farmer AA, Chen CF, Jones DC, Chen PL, Lee WH . (1996). BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner. Cancer Res 56: 3168–3172.

    CAS  PubMed  Google Scholar 

  • Coqueret O . (2002). Linking cyclins to transcriptional control. Gene 299: 35–55.

    Article  CAS  Google Scholar 

  • Cortez D, Wang Y, Qin J, Elledge SJ . (1999). Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286: 1162–1166.

    Article  CAS  Google Scholar 

  • de La Fuente C, Santiago F, Chong SY, Deng L, Mayhood T, Fu P et al. (2000). Overexpression of p21(waf1) in human T-cell lymphotropic virus type 1-infected cells and its association with cyclin A/cdk2. J Virol 16: 7270–7283.

    Article  Google Scholar 

  • Fabbro M, Rodriguez JA, Baer R, Henderson BR . (2002). BARD1 induces BRCA1 intranuclear foci formation by increasing RING-dependent BRCA1 nuclear import and inhibiting BRCA1 nuclear export. J Biol Chem 277: 21315–21324.

    Article  CAS  Google Scholar 

  • Fan S, Ma YX, Wang C, Yuan RQ, Meng Q, Wang JA et al. (2002). p300 Modulates the BRCA1 inhibition of estrogen receptor activity. Cancer Res 62: 141–151.

    CAS  PubMed  Google Scholar 

  • Hejna M, Schmidinger M, Raderer M . (2002). The clinical role of somatostatin analogues as antineoplastic agents: much ado about nothing? Ann Oncol 13: 653–668.

    Article  CAS  Google Scholar 

  • Hillion J, Le Coniat M, Jonveaux P, Berger R, Bernard OA . (1997). AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily. Blood 90: 3714–3719.

    CAS  PubMed  Google Scholar 

  • Katoh M, Katoh M . (2004). Human FOX gene family. Int J Oncol 25: 1495–1500.

    CAS  PubMed  Google Scholar 

  • Kehn K, Deng L, de la Fuente C, Strouss K, Wu K, Maddukuri A et al. (2004). The role of cyclin D2 and p21/waf1 in human T-cell leukemia virus type 1 infected cells. Retrovirology 1: 6.

    Article  PubMed Central  Google Scholar 

  • Lacroix M, Leclercq G . (2004). Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat 83: 249–289.

    Article  CAS  Google Scholar 

  • Lin L, Miller CT, Contreras JI, Prescott MS, Dagenais SL, Wu R et al. (2002). The hepatocyte nuclear factor 3 alpha gene, HNF3alpha (FOXA1), on chromosome band 14q13 is amplified and overexpressed in esophageal and lung adenocarcinomas. Cancer Res 62: 5273–5279.

    CAS  PubMed  Google Scholar 

  • Mark WY, Liao JC, Lu Y, Ayed A, Laister R, Szymczyna B et al. (2005). Characterization of segments from the central region of BRCA1: an intrinsically disordered scaffold for multiple protein–protein and protein–DNA interactions? J Mol Biol 345: 275–287.

    Article  CAS  Google Scholar 

  • Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F . (2004). Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature 430: 226–231.

    Article  CAS  Google Scholar 

  • Moisan A, Gaudreau L . (2006). The BRCA1 COOH-terminal region acts as an RNA polymerase II carboxyl-terminal domain kinase inhibitor that modulates p21WAF1/CIP1 expression. J Biol Chem 281: 21119–21130.

    Article  CAS  Google Scholar 

  • Montminy M, Brindle P, Arias J, Ferreri K, Armstrong R . (1996). Regulation of somatostatin gene transcription by cyclic adenosine monophosphate. Metabolism 45: 4–7.

    Article  CAS  Google Scholar 

  • Mullan PB, Quinn JE, Harkin DP . (2006). The role of BRCA1 in transcriptional regulation and cell cycle control. Oncogene 25: 5854–5863.

    Article  CAS  Google Scholar 

  • Nakamura T, Furukawa Y, Nakagawa H, Tsunoda T, Ohigashi H, Murata K et al. (2004). Genome-wide cDNA microarray analysis of gene expression profiles in pancreatic cancers using populations of tumor cells and normal ductal epithelial cells selected for purity by laser microdissection. Oncogene 23: 2385–2400.

    Article  CAS  Google Scholar 

  • Pao GM, Janknecht R, Ruffner H, Hunter T, Verma IM . (2000). CBP/p300 interact with and function as transcriptional coactivators of BRCA1. Proc Natl Acad Sci USA 97: 1020–1025.

    Article  CAS  Google Scholar 

  • Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M . (2001). Direct DNA binding by Brca1. Proc Natl Acad Sci USA 98: 6086–6091.

    Article  CAS  Google Scholar 

  • Rosen EM, Fan S, Ma Y . (2006). BRCA1 regulation of transcription. Cancer Lett 236: 175–185.

    Article  CAS  Google Scholar 

  • Rosen EM, Fan S, Pestell RG, Goldberg ID . (2003). BRCA1 gene in breast cancer. J Cell Physiol 196: 19–41.

    Article  CAS  Google Scholar 

  • Ruffner H, Jiang W, Craig AG, Hunter T, Verma IM . (1999). BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site. Mol Cell Biol 19: 4843–4854.

    Article  CAS  PubMed Central  Google Scholar 

  • Santiago F, Clark E, Chong S, Molina C, Mozafari F, Mahieux R et al. (1999). Transcriptional up-regulation of the cyclin D2 gene and acquisition of new cyclin-dependent kinase partners in human T-cell leukemia virus type 1-infected cells. J Virol 73: 9917–9927.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Soni R, Muller L, Furet P, Schoepfer J, Stephan C, Zumstein-Mecker S et al. (2000). Inhibition of cyclin-dependent kinase 4 (Cdk4) by fascaplysin, a marine natural product. Biochem Biophys Res Commun 275: 877–884.

    Article  CAS  Google Scholar 

  • Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG . (2002). FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res 62: 4773–4780.

    CAS  PubMed  Google Scholar 

  • Wang C, Fan S, Li Z, Fu M, Rao M, Ma Y et al. (2005). Cyclin D1 antagonizes BRCA1 repression of estrogen receptor alpha activity. Cancer Res 65: 6557–6567.

    Article  CAS  Google Scholar 

  • Wang H, Shao N, Ding QM, Cui J, Reddy ES, Rao VN . (1997). BRCA1 proteins are transported to the nucleus in the absence of serum and splice variants BRCA1a, BRCA1b are tyrosine phosphoproteins that associate with E2F, cyclins and cyclin dependent kinases. Oncogene 15: 143–157.

    Article  CAS  Google Scholar 

  • Zheng L, Annab LA, Afshari CA, Lee WH, Boyer TG . (2001). BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor. Proc Natl Acad Sci USA 98: 9587–9592.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Tanya Paull for the pDC-GST-BRCA1 constructs, Dr Doris German for the cyclin D1 construct and Dr Luke O Dannenberg for critically reviewing this manuscript. K Kehn was supported by a predoctoral research fellowship from the DOD Breast Cancer Research Program (DAMD17-03-1-0198). This work was supported in part by grants from the GWU REF funds to FK and Akos Vertes; Snyder award, and NIH grants AI065236, AI043894 to FK.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The George Washington University, Washington, DC, USA

    K Kehn, R Berro, A Alhaj, W-I Yeh, Z Klase, R Van Duyne, S Fu & F Kashanchi

  2. Department of Microbiology, Institute for Proteomics Technology and Applications, The George Washington University, Washington, DC, USA

    M E Bottazzi & F Kashanchi

  3. Department of Biochemistry, The Institute for Genomic Research (TIGR), Rockville, MD, USA

    F Kashanchi

Authors
  1. K Kehn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Berro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Alhaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M E Bottazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W-I Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Z Klase
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Van Duyne
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F Kashanchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Kashanchi.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kehn, K., Berro, R., Alhaj, A. et al. Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells. Oncogene 26, 5060–5069 (2007). https://doi.org/10.1038/sj.onc.1210319

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210319

Keywords

This article is cited by

Search

Advanced search

Quick links