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 Paper
  • Published:

Disruption of BRCA1 LXCXE motif alters BRCA1 functional activity and regulation of RB family but not RB protein binding

Oncogene volume 20, pages 4827–4841 (2001)Cite this article

Abstract

The tumor suppressor activity of the BRCA1 gene product is due, in part, to functional interactions with other tumor suppressors, including p53 and the retinoblastoma (RB) protein. RB binding sites on BRCA1 were identified in the C-terminal BRCT domain (Yarden and Brody, 1999) and in the N-terminus (aa 304–394) (Aprelikova et al., 1999). The N-terminal site contains a consensus RB binding motif, LXCXE (aa 358–362), but the role of this motif in RB binding and BRCA1 functional activity is unclear. In both in vitro and in vivo assays, we found that the BRCA1:RB interaction does not require the BRCA1 LXCXE motif, nor does it require an intact A/B binding pocket of RB. In addition, nuclear co-localization of the endogenous BRCA1 and RB proteins was observed. Over-expression of wild-type BRCA1 (wtBRCA1) did not cause cell cycle arrest but did cause down-regulation of expression of RB, p107, p130, and other proteins (e.g., p300), associated with increased sensitivity to DNA-damaging agents. In contrast, expression of a full-length BRCA1 with an LXCXE inactivating mutation (LXCXE→RXRXH) failed to down-regulate RB, blocked the down-regulation of RB by wtBRCA1, induced chemoresistance, and abrogated the ability of BRCA1 to mediate tumor growth suppression of DU-145 prostate cancer cells. wtBRCA1-induced chemosensitivity was partially reversed by expression of either Rb or p300 and fully reversed by co-expression of Rb plus p300. Our findings suggest that: (1) disruption of the LXCXE motif within the N-terminal RB binding region alters the biologic function of BRCA1; and (2) over-expression of BRCA1 inhibits the expression of RB and RB family (p107 and p130) proteins.

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
Figure 9
Figure 10
Figure 11

Similar content being viewed by others

References

  • Alley MC, Scudieco DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR . 1988 Cancer Res. 48: 589–601

  • Aprelikova ON, Fang BS, Meissner EG, Cotter S, Campbell M, Kuthiala A, Besho M, Jensen RA, Liu ET . 1999 Proc. Natl. Acad. Sci. USA 96: 11866–11871

  • Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T . 1998 Nature 391: 597–601

  • Carroll AG, Voeller HJ, Sugars L, Gelmann EP . 1993 Prostate 23: 123–134

  • Chai YL, Cui J, Shao N, Shyam E, Reddy P, Rao VN . 1999 Oncogene 18: 263–268

  • Chen CF, Li S, Chen Y, Chen PL, Sharp ZD, Lee WH . 1996 J. Biol. Chem. 271: 32863–32868

  • Cress WD, Johnson DG, Nevins JR . 1993 Mol. Cell. Biol. 13: 6314–6325

  • Dignam JD, Lebovitz RM, Roeder RG . 1983 Nucleic Acids Res. 5: 1475–1489

  • Doostzadeh-Cizeron J, Evans R, Yin S, Goodrich DW . 1999 Mol. Cell. Biol. 10: 3251–3261

  • Fan S, El-Deiry WS, Bae I, Freeman J, Jondle D, Bhatia K, Fornace AJ, Magrath I, Kohn KW, O'Connor PM . 1994 Cancer Res. 54: 5824–5830

  • Fan S, Wang J-A, Meng Q, Yuan R-Q, Ma YX, Erdos MR, Pestell RG, Yuan F, Auborn KJ, Goldberg ID, Rosen EM . 1999 Science 284: 1354–1356

  • Fan S, Wang J-A, Yuan R-Q, Ma YX, Meng Q, Goldberg ID, Rosen EM . 1998 Oncogene 16: 3069–3083

  • Field SJ, Tsai FY, Kuo F, Zubiaga AM, Kaelin Jr WG, Livingston DM, Orkin SH, Greenberg ME . 1996 Cell 85: 549–561

  • Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE . 1994 Lancet 343: 692–695

  • Freundlieb S, Baron U, Bonin AL, Gossen M, Bujard H . 1997 Methods Enzymol. 283: 159–173

  • Gowen LC, Avrutskaya AV, Latour AM, Koller BH, Leadon SA . 1998 Science 281: 1009–1012

  • Grant DS, Kleinman HK, Goldberg ID, Bhargava M, Nickoloff BJ, Polverini P, Rosen EM . 1993 Proc. Natl. Acad. Sci. USA 90: 1937–1941

  • Hakem R, de la Pomba JL, Sirard C, Mo R, Woo M, Hakem A, Wakeham A, Potter J, Reitmair A, Billia F, Firpo E, Hui CC, Roberts J, Rossant J, Mak TW . 1996 Cell 85: 1009–1023

  • Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C, Christians FC, Ellisen LW, Maheswaran S, Oliner JD, Haber DA . 1999 Cell 97: 575–586

  • Herrmann M, Lorenz H-M, Voll R, Grunke M, Weith W, Kalden JR . 1994 Nucleic Acids Res. 22: 5506–5507

  • Holt JT, Thompson ME, Szabo C, Robinson-Benion C, Arteaga CL, King M-C, Jensen RA . 1996 Nat. Genet. 12: 298–302

  • Hsieh JK, Federsdorf S, Kouzarides T, Martin K, Lu X . 1997 Genes Dev. 11: 1840–1852

  • Kaelin Jr WG, Pallor DC, DeCaprio JA, Kaye FJ, Livingston DM . 1991 Cell 64: 521–532

  • Lee JO, Russo AA, Pavletich NP . 1998 Nature 391: 859–865

  • Lin SC, Shapek SX, Lee EY . 1996 Semin. Cancer Biol. 7: 279–289

  • Magnaghi-Jaulin L, Groisman R, Naguibneva I, Robin P, Lorain S, Le Villain JP, Troalen F, Trouche D, Harel-Bellan A . 1998 Nature 391: 601–605

  • Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cichran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden, R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Norris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannon-Albright L, Goldgar D, Wiseman R, Kamb A, Skolnick MK . 1994 Science 266: 66–71

  • Monteiro AN, August A, Hanafusa H . 1996 Proc. Natl. Acad. Sci. USA 93: 13595–13599

  • Ouichi T, Monteiro AN, August A, Aaronson SA, Hanafusa H . 1998 Proc. Natl. Acad. Sci. USA 95: 2302–2306

  • Rajan JV, Wang M, Marquis ST, Chodosh L . 1996 Proc. Nat. Acad. Sci. USA 93: 13078–13083

  • Pao GM, Janknecht R, Ruffner H, Hunter T, Verma IM . 2000 Proc. Natl. Acad. Sci. USA 97: 1020–1050

  • Pestell RG, Albanese C, Lee RJ, Watanabe G, Moran E, Johnson J, Jameson JL . 1996 Cell. Growth Differ. 7: 1337–1344

  • Pomerantz J, Schreiber Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA . 1998 Cell 92: 713–723

  • Quelle DE, Zindy F, Ashmun RA, Sherr CD . 1995 Cell 83: 993–1000

  • Samuelson AV, Lowe SW . 1997 Proc. Natl. Acad. Sci. USA 94: 12094–12099

  • Sarkar FH, Sakr W, Li YW, Macoska J, Ball DE, Crissman JD . 1992 Prostate 21: 145–152

  • Scully R, Chen J, Plug A, Xiao P, Weaver D, Feunteau J, Ashley T, Livingston D . 1997 Cell 88: 265–275

  • Shao N, Chai YL, Shyam E, Reddy P, Rao VM . 1996 Oncogene 13: 1–7

  • Somasundaram K, MacLachlan TK, Burns TF, Sgagias M, Cowan KH, Weber BL, El-Deiry WS . 1999 Oncogene 18: 6605–6614

  • Somasundaram K, Zhang H, Zeng Y-X, Houvras Y, Peng Y, Zhang H, Wu GS, Licht JD, Weber BL, El-Deiry WS . 1997 Nature 389: 187–190

  • Streuwing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA . 1997 New Engl. J. Med. 336: 1401–1408

  • Tao W, Levine AJ . 1999 Proc. Natl. Acad. Sci. USA 96: 6937–6941

  • Thompson ME, Jensen RA, Obermiller PS, Page DL, Holt JT . 1995 Nat. Genet. 9: 444–450

  • Tirkkonen M, Johannson O, Agnarsson BA, Olsson H, Ingvarsson S, Karbu R, Tanner M, Isola J, Barkardottir RB, Borg A, Kallioniemi OP . 1997 Cancer Res. 57: 1222–1227

  • Tsai KY, Hu Y, Macleod KF, Crowley D, Yamasaki L, Jacks T . 1998 Mol. Cell. 2: 293–304

  • Wang CY, Petryniak B, Thompson CB, Kaelin WG, Leiden JM . 1993 Science 260: 1330–1335

  • Wang H, Shao N, Ding OM, Qui J-Q, Reddy ESP, Rao VN . 1997 Oncogene 15: 143–147

  • Yarden RI, Brody LC . 1999 Proc. Natl. Acad. Sci. USA 96: 4983–4988

  • Yu X, Wu LC, Bowcock AM, Aronheim A, Baer R . 1998 J. Biol. Chem. 273: 25388–25392

  • Zalvide J, DeCaprio JA . 1995 Mol. Cell. Biol. 15: 5800–5810

  • Zhang H, Somasundaram K, Peng Y, Tian H, Zhang H, Bi D, Weber BL, El-Deiry WS . 1998 Oncogene 16: 1713–1721

Download references

Acknowledgements

This research was supported in part by grants from the USPHS (R01-ES09169, RO1-CA80000, and RO1-CA82599), the Elsa U. Pardee Cancer Foundation of Michigan, the New York State Department of Health (EMR), a U.S. Army Career Development Award to S Fan, and a Long Island Jewish Hospital Competitive Pool Award (S Fan).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, New York, 11040, NY, USA

    Saijun Fan, Ren-qi Yuan, Yong Xian Ma, Jingbo Xiong, Qinghui Meng, Itzhak D Goldberg & Eliot M Rosen

  2. Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Room 3A14, Bethesda, 20892, Maryland, MD, USA

    Michael Erdos

  3. Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, NY, USA

    Jian-Nian Zhao, Richard G Pestell & Eliot M Rosen

  4. Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, Bronx, 10461, NY, USA

    Richard G Pestell

  5. Department of Radiation Oncology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, NY, USA

    Eliot M Rosen

  6. Division of Hormone-Dependent Tumor Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, NY, USA

    Jian-Nian Zhao, Richard G Pestell & Eliot M Rosen

Authors
  1. Saijun Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ren-qi Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong Xian Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jingbo Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qinghui Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Erdos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian-Nian Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Itzhak D Goldberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Richard G Pestell
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Eliot M Rosen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Saijun Fan or Eliot M Rosen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fan, S., Yuan, Rq., Ma, Y. et al. Disruption of BRCA1 LXCXE motif alters BRCA1 functional activity and regulation of RB family but not RB protein binding. Oncogene 20, 4827–4841 (2001). https://doi.org/10.1038/sj.onc.1204666

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204666

Keywords

This article is cited by

Search

Advanced search

Quick links