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:

BRCA1 signals ARF-dependent stabilization and coactivation of p53

Oncogene volume 18, pages 6605–6614 (1999)Cite this article

Abstract

The hereditary breast and ovarian tumor suppressor BRCA1 can activate p53-dependent gene expression. We show here that BRCA1 increases p53 protein levels through a post-transcriptional mechanism. BRCA1-stabilized p53 has increased sequence-specific DNA-binding and transcriptional activity. BRCA1 does not stabilize p53 in p14ARF-deficient cells. A deletion mutant of BRCA1 which inhibits p53-dependent transcription confers resistance to topoisomerase II-targeted chemotherapy. Our results suggest that BRCA1 may trigger the p53 pathway through two potentially separate mechanisms: accumulation of p53 through a direct or indirect induction of p14ARF as well as direct transcriptional coactivation of p53. BRCA1 may also enhance chemosensitivity and repair of DNA damage through binding to and coactivation of p53.

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

Similar content being viewed by others

References

  • Adams PD and Kaelin WG Jr. . 1995 Sem. Cancer Biol. 6: 99–108.

  • Baker, SJ, Markowitz S, Fearon ER, Willson JK and Vogelstein B. . 1990 Science 249: 912–915.

  • Bates S, Phillips AC, Clark PA, Stott F, Peters G, Ludwig RL and Vousden KH. . 1998 Nature 395: 124–125.

  • Blagosklonny MV and El-Deiry WS. . 1996 Int. J. Cancer 67: 386–392.

  • Chapman MS and Verma I. . 1996 Nature 382: 678–679.

  • de Stanchina E, McCurrach ME, Zindy F, Shieh S-F, Ferbeyre G, Samuelson AV, Prives C, Roussel MF, Sherr CH and Lowe SW. . 1998 Genes Dev. 12: 2434–2442.

  • Easton DF, Ford D and Bishop DT. . 1995 Am. J. Hum. Genet. 56: 265–271.

  • El-Deiry WS. . 1998 Semin. Cancer Biol. 8: 345–357.

  • El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B. . 1993 Cell 75: 817–825.

  • El-Deiry WS, Tokino T, Waldman T, Oliner JD, Velculescu VE, Burrell M, Hill DE, Healy E, Rees JL, Hamilton SR, Kinzler KW and Vogelstein B. . 1995 Cancer Res. 55: 2910–2919.

  • El-Deiry WS, Harper JW, Oconnor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, Wang YS, Wiman KG, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW and Vogelstein B. . 1994 Cancer Res. 54: 1169–1174.

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

  • Futreal PA, Liu O, Shattuck-Eidens D, Cochran C, Harshmann K, Tavtigian S, Bennett LM, Hasgen-Strano A, Swenson J, Miki Y, Eddington K, McClure M, Frye C, Weaver-Feldhaus J, Ding W, Gholami Z, Soederkvist P, Terry L, Jhanwar S, Berchuck A, Iglehart JD, Marks J, Ballinger DG, Barrett JC, Skolnick MH, Kamb A and Wiseman R. . 1994 Science 266: 120–122.

  • Garcia-Patino E, Gomendio B, Lleonart M, Silva JM, Garcia JM, Provencio M, Cubedo R, Espana P, Ramon y Cajal S, Bonilla F. . 1998 Can. Genet. Cytogenet. 104: 119–123.

  • 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 and Mak TW. . 1996 Cell 85: 1009–1023.

  • Hall JM, Lee MK, Newman B, Morrow E, Anderson LA, Huey B and King M-C. . 1990 Science 250: 1684–1689.

  • Katayose D, Godas J, Nguyen H, Srinivatava S, Cowan KH and Seth P. . 1995 Clin. Cancer Res. 1: 889–897.

  • La Thange NB. . 1994 Curr. Opin. Cell Biol. 6: 443–450.

  • Li S, Chen PL, Subramanian T, Chinnadurai G, Tomlinson G, Osborne CK, Sharp ZD and Lee WH. . 1999 J. Biol. Chem. 274: 11334–11338.

  • Lovering R, Hanson IM, Borden KLB, Maetin S, O'Reilly NJ, Evan GI, Rahman D, Pappin DJC, Trowsdale J and Freemont PS. . 1993 Proc. Natl. Acad. Sci. USA 90: 2112–2116.

  • Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu C, Cochran 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 and Skolnick MH. . 1994 Science 266: 66–71.

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

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

  • Palmero I, Pantoja C and Serrano M. . 1998 Nature 395: 125–126.

  • Polyak K, Waldman T, He TC, Kinzler KW and Vogelstein B. . 1996 Genes Dev. 10: 1945–1952.

  • Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Livingston DM and Parvin JD. . 1997a Proc. Natl. Acad. Sci. USA 94: 5605–5610.

  • Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T and Livingston DM. . 1997b Cell 88: 265–275.

  • Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J and Livingston DM. . 1997c Cell 90: 425–435.

  • Smith PD, Crosslan S, Parker G, Osin P, Brooks L, Waller J, Philp E, Crompton BA, Gusterson BA, Allday MJ and Crook T. . 1999 Oncogene 18: 2451–2459.

  • Somasundaram K, Jayaraman G, Williams T, Moran E, Frisch S and Thimmapaya B. . 1996 Proc. Natl. Acad. Sci. USA 93: 3088–3093.

  • Somasundaram K and El-Deiry WS. . 1997 Oncogene 14: 1047–1057.

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

  • Stone S, Jiang P, Dayanath P, Tavtgian SV, Katcher H, Parry D, Peters G and Kamb A . 1995 Cancer Res. 55: 2988–2994.

  • Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brooks S, Palmero I, Ryan K, Hara E, Vousden KH and Peters G. . 1988 EMBO J. 17: 5001–5014.

  • Szabo CI and King MC. . 1995 Hum. Mol. Genet. 4: 1811–1817.

  • Thomas JE, Smith M, Tonkinson JL, Rubinfled B and Polakis P. . 1997 Cell Growth Differ 8: 801–809.

  • Weinberg RA. . 1995 Cell 81: 323–330.

  • Zeng YX, Somasundaram K and El-Deiry WS. . 1997 Nature Genet. 15: 78–82.

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

  • Zindy F, Eischen DH, Randle DH, Kamijo T, Cleveland JL, Sherr CR and Roussel MF. . 1998 Genes Dev. 12: 2424–2433.

Download references

Acknowledgements

The authors thank MF Roussel and CH Sherr for providing p19ARF−/− mouse embryo fibroblasts. This work was supported in part by NIH Grant # CA7641701. WS El-Deiry is an Assistant Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Kumaravel Somasundaram, Timothy K MacLachlan, Timothy F Burns & Wafik S El-Deiry

  2. Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Timothy K MacLachlan & Wafik S El-Deiry

  3. Department of Medicine and Genetics, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Kumaravel Somasundaram, Barbara L Weber & Wafik S El-Deiry

  4. Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Wafik S El-Deiry

  5. Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, PA, USA

    Barbara L Weber & Wafik S El-Deiry

  6. Medicine Branch, National Cancer Institute, Building 10, Room 12N22, Bethesda, 20892, Maryland, MD, USA

    Magda Sgagias & Kenneth H Cowan

Authors
  1. Kumaravel Somasundaram
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timothy K MacLachlan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Timothy F Burns
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Magda Sgagias
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenneth H Cowan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Barbara L Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wafik S El-Deiry
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Somasundaram, K., MacLachlan, T., Burns, T. et al. BRCA1 signals ARF-dependent stabilization and coactivation of p53. Oncogene 18, 6605–6614 (1999). https://doi.org/10.1038/sj.onc.1203284

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203284

Keywords

This article is cited by

Search

Advanced search

Quick links