Abstract
Loss or lowered expression of BRCA1 in non-familial breast cancer has been shown in several recent studies. Understanding how BRCA1 expression is regulated should provide new insights into the role of BRCA1 in sporadic breast cancer. We have recently identified a critical 18-base pair (bp) DNA element within the minimal BRCA1 promoter whereupon the formation of a specific protein-DNA complex and transcription of BRCA1 is dependent. We now report a non tissue-specific transcriptional repressor activity, located more than 500 bp into the first intron of BRCA1. Progressive deletions from the 3′-end of intron 1 and reporter gene assays localized the repressor activity to an 83-bp region. Electrophoretic mobility shift assays with this 83 bp DNA and various sub-fragments of it showed binding of nuclear proteins to a 36 bp BstNI–BseRI fragment. Functional transcriptional repression by this 36 bp DNA could be conferred on a heterologous thymidine kinase promoter. Analysis of multiple reporter gene constructs containing the BRCA1 genomic region driving transcription in both directions suggests that the putative negative regulatory element functions to block transcription only in the BRCA1 direction, although the promoter is shared by the divergently transcribed NBR2 gene.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Anderson SF, Schlegel BP, Nakajima T, Wolpin ES and Parvin JD. . 1998 Nat. Genet. 19: 254–256.
Andres JL, Fan S, Turkel GJ, Wang J-A, Twu N-F, Yuan R-Q, Lamszus K, Goldberg ID and Rosen EM. . 1998 Oncogene 16: 2229–2241.
Berchuck A, Heron K-A, Carney ME, Lancaster JM, Fraser EG, Vinson VL, Deffenbaugh AM, Miron A, Marks JR, Futreal PA and Frank TS. . 1998 Clin Cancer Res. 4: 2433–2437.
Bertwistle D and Ashworth A. . 1998 Curr. Opin. Genet. Dev. 8: 14–20.
Blackshear PE, Goldsworthy SM, Foley JF, McAllister KA, Bennett LM, Collins NK, Bunch DO, Brown P, Wiseman RW and Davis BJ. . 1998 Oncogene 16: 61–68.
Budhram-Mahadeo V, Ndisang D, Ward T, Weber BL and Latchman DS. . 1999 Oncogene 18: 6684–6691.
Casey G. . 1997 Curr. Opin. Oncol. 9: 88–93.
Catteau A, Harris WH, Xu C-F and Solomon E. . 1999 Oncogene 18: 1957–1965.
Chapman MS and Verma IM. . 1996 Nature 382: 678–679.
Chen C and Okayama H. . 1987 Mol. Cell. Biol. 7: 2745–2752.
Chen Y, Farmer AA, Chen C-F, Jones DC, Chen P-L and Lee W-H. . 1996 Cancer Res. 56: 3168–3172.
Cornelis R, Neuhausen SL, Johansson O, Arason A, Kelsell D, Ponder BAJ, Tonin P, Hamann U, Lindblom A, Lalle P, Longy M, Olah E, Scherneck S, Bignon Y-J, Sobol H, Chang-Claude J, Larsson C, Spurr N, Borg A, Barkardottir RB, Narod S, Devilee P and the Breast Cancer Linkage Consortium. . 1995 Genes Chrom. Cancer 13: 203–210.
Cressman VL, Backlund DC, Avrutskaya AV, Leadon SA, Godfrey V and Koller BH. . 1999 Mol. Cell. Biol. 19: 7061–7075.
Dignam JD, Leibovitz RM and Roeder RG. . 1983 Nucleic Acids Res. 11: 1475–1489.
Deng C-X and Scott F. . (2000) Oncogene 19: 1059–1064.
Dobrovic A and Simpfendorfer D. . 1997 Cancer Res. 57: 3347–3350.
Fan S, Wang J-A, Yuan R, Ma Y, Meng Q, Erdos MR, Pestell RG, Yuan F, Auborn KJ, Goldberg ID and Rosen EM. . 1999 Science 284: 1354–1356.
Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BAJ, Gayther SA, Birch JM, Lindblom A, Stoppa-Lyonnet D, Bignon Y, Borg A, Hamann U, Haites N, Scott RJ, Maugard CM, Vasen H and the Breast Cancer Linkage Consortium. . 1998 Am. J. Hum. Genet. 62: 676–689.
Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigan S, Bennett LM, Haugen-Strano A, Swensen J, Miki Y, Eddington K, McClure M, Frye C, Weaver-Feldhaus J, Ding W, Gholami Z, Soderkvist 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.
Gudas JM, Li T, Nguyen H, Jensen D, Rauscher III FJ and Cowan KH. . 1996 Cell Growth Differ. 7: 717–723.
Haile DT and Parvin JD. . 1999 J. Biol. Chem. 274: 2113–2117.
Holt JT, Thompson ME, Szabo C, Robinson-Benion C, Arteaga CL, King M-C and Jensen RA. . 1996 Nat. Genet. 12: 298–302.
Hosking L, Trowsdale J, Nicolai H, Solomon E, Foulkes W, Stamp G, Signer E and Jeffery A. . 1995 Nat. Genet. 9: 343–344.
Husain A, He G, Venkatraman ES and Spriggs DR. . 1998 Cancer Res. 58: 1120–1123.
Khoo U-S, Ozcelik H, Cheung ANY, Chow LWC, Ngan HYS, Done SJ, Liang ACT, Chan VWY, Au GKH, NgW-F, Poon CSP, Leung Y-F, Loong F, Ip P, Chan GSW, Andrulis IL, Lu J and Ho FCS. . 1999 Oncogene 18: 4643–4646.
Lane TF, Deng C, Elson A, Lyu MS and Kozak CA. . 1995 Genes Dev. 9: 2712–2722.
Luckow B and Schutz G. . 1987 Nucleic Acids Res. 15: 5490.
MacGregor GR and Caskey CT. . 1989 Nucleic Acids Res. 17: 2365.
Mancini DN, Rodenhiser DI, Ainsworth PJ, O'Malley FP, Singh SM, Xing W and Archer TK. . 1998 Oncogene 16: 1161–1169.
Magdinier F, Ribieras S, Lenoir GM, Frappart L and Dante R. . 1998 Oncogene 17: 3169–3176.
Magdinier F, Venezia ND, Lenoir GM, Frappart L and Dante R. . 1999 Oncogene 18: 4039–4043.
Marquis ST, Rajan JV, Wynshaw-Boris A, Xu J, Yin G-Y, Abel KJ, Weber BL and Chodosh LA. . 1995 Nat. Genet. 11: 17–26.
Merajver SD, Pham TM, Caduff RF, Chen M, Poy EL, Cooney KA, Weber BL, Collins FS, Johnston C and Frank TS. . 1995 Nat. Genet. 9: 439–443.
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigan S, Liu Q, 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 ANA, August A and Hanafusa H. . 1996 Proc. Natl. Acad. Sci. USA 93: 13595–13599.
Moynahan ME, Chiu JW, Koller BH and Jasin M. . 1999 Mol. Cell. 4: 511–518.
Neuhausen SL and Marshall CJ. . 1994 Cancer Res. 54: 6069–6072.
Ouchi T, Monteiro ANA, August A, Aaronson SA and Hanafusa H. . 1998 Proc. Natl. Acad. Sci. USA 95: 2302–2306.
Pao GM, Janknecht R, Ruffner H, Hunter T and Verma IM. . 2000 Proc. Natl. Acad. Sci. USA 97: 1020–1025.
Philipsen S and Suske G. . 1999 Nucleic Acids Res. 27: 2991–3000.
Rao VN, Shao N, Ahmad M and Reddy ESP. . 1996 Oncogene 12: 523–528.
Rice JC, Massey-Brown KS and Futscher BW. . 1998 Oncogene 17: 1807–1812.
Ruffner H and Verma IM. . 1997 Proc. Natl. Acad. Sci. USA 94: 7138–7143.
Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, Livingston DM and Parvin JD. . 1997 Proc. Natl. Acad. Sci. USA 94: 5605–5610.
Scully R, Ganesan S, Vlasakova K, Chen J, Socolovsky M and Livingston DM. . 1999 Mol. Cell. 4: 1093–1099.
Sharrocks AD, Brown AL, Ling Y and Yates PR. . 1997 Int. J. Biochem. Cell. Biol. 29: 1371–1387.
Shen S-X, Weaver Z, Xu X, Li C, Weinstein M, Chen L, Guan X-Y, Ried T and Deng C-X. . 1998 Oncogene 17: 3115–3124.
Smith SA, Easton DF, Evans DGR and Ponder BAJ. . 1992 Nat. Genet. 2: 128–131.
Somasundaram K, Zhang H, Zeng Y-X, Houvras Y, Peng Y, Zhang H, Wu GS, Licht JD, Weber BL and El-Deiry WS. . 1997 Nature 389: 187–190.
Sourvinos G and Spandidos DA. . 1998 Biochem. Biophys. Res. Comm. 245: 75–80.
Suen T-C and Hung M-C. . 1990 Mol. Cell. Biol. 10: 6306–6315.
Suen T-C and Goss PE. . 1999 J. Biol. Chem. 274: 31297–31304.
Suen T-C and Goss PE. . 2000 J. Biol. Chem. 275: 6600–6607.
Thakur S and Croce CM. . 1999 J. Biol. Chem. 274: 8837–8843.
Thompson ME, Jensen RA, Obermiller PS, Page DL and Holt JT. . 1995 Nat. Genet. 9: 444–450.
van der Looij M, Cleton-Jansen A-M, van Eijk R, Morreau H, van Vliet M, Kuipers-Dijkshoorn N, Olah E, Cornelisse CJ and Devilee P. . 2000 Genes Chrom. Cancer 27: 295–302.
Vaughn JP, Davis PL, Jarboe MD, Huper G, Evans AC, Wiseman RW, Berchuck A, Iglehart JD, Futreal PA and Marks JR. . 1996 Cell Growth Differ. 7: 711–715.
Wilson CA, Ramos L, Villasenor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen J-J, Scully R, Livingston D, Zuch RH, Kanter MH, Cohen S, Calzone FJ and Slamon DJ. . 1999 Nat. Genet. 21: 236–240.
Xu C-F, Brown MA, Chambers JA, Griffiths B, Nicolai H and Solomon E. . 1995 Hum. Mol. Genet. 4: 2259–2264.
Xu C-F, Chambers JA and Solomon E. . 1997a J. Biol. Chem. 272: 20994–20997.
Xu C-F, Brown MA, Nicolai H, Chambers JA, Griffiths BL and Solomon E. . 1997b Hum. Mol. Genet. 6: 1057–1062.
Xu X, Wagner K-U, Larson D, Weaver Z, Li C, Ried T, Hennighausen L, Wynshaw-Boris A and Deng C-X. . 1999 Nat. Genet. 22: 37–43.
Yarden RI and Brody LC. . 1999 Proc. Natl. Acad. Sci. USA 96: 4983–4988.
Zhang H, Somasundaram K, Peng Y, Tian H, Zhang H, Bi D, Weber BL and El-Deiry WS. . 1998 Oncogene 16: 1713–1721.
Acknowledgements
This work was supported by a grant from the Breast Cancer Prevention Program of the Toronto Hospital.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Suen, TC., Goss, P. Identification of a novel transcriptional repressor element located in the first intron of the human BRCA1 gene. Oncogene 20, 440–450 (2001). https://doi.org/10.1038/sj.onc.1204078
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204078
Keywords
This article is cited by
-
DBC1 is over-expressed and associated with poor prognosis in colorectal cancer
International Journal of Clinical Oncology (2014)
-
Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation
Oncogene (2012)
-
Regulation of BRCA1 expression and its relationship to sporadic breast cancer
Breast Cancer Research (2002)