Abstract
A substantial proportion of familial breast cancers have mutations within the BRCA2 gene. The product of this gene has been implicated in DNA repair and in the regulation of transcription. We have previously identified at the amino-terminus of BRCA2 a transcriptional activation domain whose importance is highlighted by the presence of predisposing mutations and in-frame deletions in breast cancer families. This activation domain shows sequence similarity to a region of c-Jun which has been defined as a binding site for the c-Jun N-terminal kinase. Here, we show that the analogous region in BRCA2 is also a binding site for a cellular kinase, although this kinase is distinct from JNK. The BRCA2 associated enzyme is able to phosphorylate residues within the BRCA2 activation domain. Consistent with this observation, we find that the activation domain of BRCA2 is phosphorylated in vivo. Our results indicate that the BRCA2 activation domain possesses a binding site for a kinase that may regulate BRCA2 activity by phosphorylation.
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References
Bannister AJ and Kouzarides T. . 1996 Nature 384: 641–643.
Chen PL, Chen CF, Chen Y, Xiao J, Sharp D and Lee WE. . 1998 Proc. Natl. Acad. Sci. USA 95: 5287–5292.
Connor F, Smith A, Wooster R, Stratton M, Dixon A, Campbell E, Tait TM, Freeman T and Ashworth A. . 1997 Hum. Mol. Genet. 6: 291–300.
Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M and Davis RJ. . 1994 Cell 76: 1025–1037.
Fuks F, Milner J and Kouzarides T. . 1998 Oncogene 17: 2531–2534.
Fuks F, Burgers WA, Brehm A, Hughes-Davies L and Kouzarides T. . 2000 Nat Genet. 24: 88–91.
Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B and Davis RJ. . 1996 EMBO J. 15: 2760–2770.
Hibi M, Lin A, Smeal T, Minden A and Karin M. . 1993 Genes Dev. 7: 2135–2148.
Marmorstein LY, Ouchi T and Aaronson SA. . 1998 Proc. Natl. Acad. Sci. USA 95: 13869–13874.
May GH, Harris F, Gillespie D and Black DM. . 1999 Genes Chromosomes Cancer 25: 407–409.
Milner J, Ponder B, Hughes Davies L, Seltmann M and Kouzarides T. . 1997 Nature 386: 772–773.
Mizuta R, LaSalle JM, Cheng HL, Shinohara A, Ogawa H, Copeland N, Jenkins NA, Lalande M and Alt FW. . 1997 Proc. Natl. Acad. Sci. USA 94: 6927–6932.
Nordling M, Karlsson P, Wahlstrom J, Engwall Y, Wallgren A and Martinsson T. . 1998 Cancer Res. 58: 1372–1375.
Patel KJ, Yu VPCC, Lee H, Corcoran A, Thistlewaite FC, Evans MJ, Colledge WH, Friedman LS, Ponder BAJ and Venkitaraman AR. . 1998 Mol. Cell 1: 347–357.
Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E, Dinh C, Sands A, Eichele G, Hasty P and Bradley A. . 1997 Nature 386: 804–810.
Suzuki A, de la Pompa JL, Hakem R, Elia A, Yoshida R, Mo R, Nishina H, Chuang T, Wakeham A, Itie A, Koo W, Billia P, Ho A, Fukumoto M, Hui CC and Mak TW. . 1997 Genes Dev. 11: 1242–1252.
Tavtigian SV, Simard J, Rommens J, Couch F, Shattuck Eidens D, Neuhausen S, Merajver S, Thorlacius S, Offit K, Stoppa Lyonnet D, Belanger C, Bell R, Berry S, Bogden R, Chen Q, Davis T, Dumont M, Frye C, Hattier T, Jammulapati S, Janecki T, Jiang P, Kehrer R, Leblanc JF, Mitchell JT, McArthur-Morrison J, Nguyen K, Peng Y, Samson C, Schroeder M, Snyder SC, Steele L, Stringfellow M, Stroup C, Swedlund B, Swensen J, Teng D, Thomas A, Tran T, Tranchant M, Weaver- Feldhaus JE, Wong AKC, Shizuya H, Eyfjord JE, Cannon-Albright L, Labrie F, Skolnick MH, Weber B, Kamb A and Goldgar DE. . 1996 Nat Genet. 12: 333–337.
Wong AKC, Pero R, Ormonde PA, Tavtigian SV and Bartel PL. . 1998 J. Biol. Chem. 272: 31941–31944.
Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C and Micklem G. . 1995 Nature 378: 789–792.
Acknowledgements
J Milner was supported by a grant from the Cancer Research Campaign; F Fuks was supported by fellowships from the European Community Training and Mobility of Researchers Fellowship and the Wiener-Anspach Fundation; L Hughes-Davies was funded by a CRC Clinical Fellowship.
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Milner, J., Fuks, F., Hughes-Davies, L. et al. The BRCA2 activation domain associates with and is phosphorylated by a cellular protein kinase. Oncogene 19, 4441–4445 (2000). https://doi.org/10.1038/sj.onc.1203793
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DOI: https://doi.org/10.1038/sj.onc.1203793
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