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Initiation of translation from a downstream in-frame AUG codon on BRCA1 can generate the novel isoform protein ΔBRCA1(17aa)

Oncogene volume 19, pages 2767–2773 (2000)Cite this article

Abstract

Expression of the breast and ovarian cancer gene BRCA1 is regulated at both the transcriptional and post-transcriptional levels. We found that the expression of the BRCA1 protein may also be regulated at the translational level. In addition to an AUG start codon at position 1, BRCA1 mRNA has a second in-frame AUG (+17) that acts as an alternative start codon to generate a novel BRCA1 protein that lacks the first 17 amino acids (ΔBRCA1(17aa)). We fused cDNAs encoding the second exon of BRCA1 of the wild-type BRCA1 gene (wt-BRCA1) and a mutated BRCA1 gene (mt-BRCA1), in which the first initiation site and its Kozak consensus sequence were abolished, with the nucleophosmin (NPM) reporter gene and used them for in vitro and in vivo translation assays. In both systems, the wt-BRCA1-NPM constructs produced two distinct proteins (18 and 16 kD) begun from the first and second AUGs. The mt-BRCA1-NPM constructs produced only the shorter 16-kD protein lacking the first 17 amino acids of the BRCA1 gene. Next, we analysed the N-terminal protein sequence of purified BRCA1 protein from normal thymocytes and found two different BRCA1 proteins, derived from translation of the first and second in-frame AUGs. Thus, BRCA1 protein expression can be regulated at the translation level in normal cells. Characterization of ΔBRCA1(17aa) may shed light on the function and regulation of BRCA1 in normal cells as well as the pathogenesis of breast and ovarian cancers.

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References

  • Bork P, Hofmann K, Bucher P, Neuwald AF, Altschul SF and Koonin EV . 1997 FASEB J 11: 68–76

  • Brown MA, Xu CF, Nicolai H, Griffiths B, Chambers JA, Black D and Solomon E . 1996 Oncogene 12: 2507–2513

  • Callebaut I and Mornon JP . 1997 FEBS Lett 400: 25–30

  • Castilla LH, Couch FJ, Erdos MR, Hoskins KF, Calzone K, Garber JE, Boyd J, Lubin MB, Deshano ML, Brody LC et al. 1994 Nat Genet 8: 387–391

  • Catteau A, Harris WH, Xu CF and Solomon E . 1999 Oncogene 18: 1957–1965

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

  • Chan WY, Liu QR, Borjigin J, Busch H, Rennert OM, Tease LA and Chan PK . 1989 Biochemistry 28: 1033–1039

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

  • Chen Y, Farmer AA, Chen CF, Jones DC, Chen PL and Lee WH . 1996 Cancer Res 56: 3168–3172

  • Colizan JE, Dun BM, Ploegh HL, Speicher DW and Wingfield PT . Curr Protocols Pro Sci New York

  • Cortez D, Wang Y, Qin J and Elledge SJ . 1999 Science 286: 1162–1166

  • Cressman VL, Backlund DC, Hicks EM, Gowen LC, Godfrey, V and Koller BH . 1999 Cell Growth Differ 10: 1–10

  • Cui JQ, Shao N, Chai Y, Wang H, Reddy ES and Rao VN . 1998 Oncol Rep 5: 591–595

  • Dobrovic A and Simpfendorfer D . 1997 Cancer Res 57: 3347–3350

  • Easton DF, Bishop DT, Ford D and Crockford GP . 1993 Am J Hum Genet 52: 678–701

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

  • Friedman LS, Ostermeyer EA, Szabo CI, Dowd P, Lynch ED, Rowell SE and King MC . 1994 Nat Genet 8: 399–404

  • Gaidano G, Ballerini P, Gong JZ, Inghirami G, Neri A, Newcomb EW, Magrath IT, Knowles DM and Dalla-Favera R . 1991 Proc Natl Acad Sci USA 88: 5413–5417

  • Haile DT and Parvin JD . 1999 J Biol Chem 274: 2113–2117

  • Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B and King MC . 1990 Science 250: 1684–1689

  • Inghirami G, Macri L, Cesarman E, Chadburn A, Zhong J and Knowles DM . 1994 Blood 83: 3581–3590

  • Irminger-Finger I, Siegel BD and Leung WC . 1999 Biol Chem 380: 117–128

  • Irminger-Finger I, Soriano JV, Vaudan G, Montesano R and Sappino AP . 1998 J Cell Biol 143: 1329–1339

  • Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, Ishov AM, Tommerup N, Vissing H, Sekido Y, Minna J, Borodovsky A, Schultz DC, Wilkinson KD, Maul GG, Barlev N, Berger SL, Prendergast GC and Rauscher FJR . 1998 Oncogene 16: 1097–1112

  • Jin Y, Xu XL, Yang MC, Wei F, Ayi TC, Bowcock AM and Baer R . 1997 Proc Natl Acad Sci USA 94: 12075–12080

  • Kleiman FE and Manley JL . 1999 Science 285: 1576–1579

  • Lee WY, Jin YT, Chang TW, Lin PW and Su IJ . 1999 Histopathology 34: 106–112

  • Lu M, Conzen SD, Cole CN and Arrick BA . 1996 Cancer Res 56: 4578–4581

  • Magdinier F, Ribieras S, Lenoir GM, Frappart L and Dante R . 1998 Oncogene 17: 3169–3176

  • Mancini DN, Rodenhiser DI, Ainsworth PJ, O'Malley FP, Singh SM, Xing W and Archer TK . 1998 Oncogene 16: 1161–1169

  • Matsudaira P . 1987 J Biol Chem 262: 10035–10038

  • Meza JE, Brzovic PS, King MC and Klevit RE . 1999 J Biol Chem 274: 5659–5665

  • Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al. 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 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

  • 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 . 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

  • Thakur S and Croce CM . 1999 J Biol Chem 274: 8837–8843

  • Thakur S, Zhang HB, Peng Y, Le H, Carroll B, Ward T, Yao J, Farid LM, Couch FJ, Wilson RB and Weber BL . 1997 Mol Cell Biol 17: 444–452

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

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

  • Wang H, Shao N, Ding QM, Cui J, Reddy ES and Rao VN . 1997 Oncogene 15: 143–157

  • Wilson CA, Ramos L, Villasenor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, Livingston D, Zuch RH, Kanter MH, Cohen S, Calzone FJ and Slamon DJ . 1999 Nat Genet 21: 236–240

  • Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A, Xu XL, Yang MC, Hwang LY, Bowcock AM and Baer R . 1996 Nat Genet 14: 430–440

  • Xu CF, Brown MA, Chambers JA, Griffiths B, Nicolai H and Solomon E . 1995 Hum Mol Genet 4: 2259–2264

  • Xu CF, Brown MA, Nicolai H, Chambers JA, Griffiths BL and Solomon E . 1997a Hum Mol Genet 6: 1057–1062

  • Xu CF, Chambers JA and Solomon E . 1997b J Biol Chem 272: 20994–20997

  • Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T, Hennighausen L, Wynshaw-Boris A and Deng CX . 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, Bi D, Weber BL and El-Deiry WS . 1998 Oncogene 16: 1713–1721

  • Zhong Q, Chen CF, Li S, Chen Y, Wang CC, Xiao J, Chen PL, Sharp ZD and Lee WH . 1999 Science 285: 747–750

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Acknowledgements

G Prolla was partially supported by training grant CA-2T32CA09454 from the National Cancer Institute. This work was also supported in part by grant NIH R21-CA66229.

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Author notes

  1. Jinsong Liu and Gabriel Prolla: The first two authors contributed equally to this work

Authors and Affiliations

  1. Department of Pathology, New York University Medical Center, New York, 10016, NY, USA

    Jinsong Liu, Agueda Rostagno, Roberto Chiarle, Helen Feiner & Giorgio Inghirami

  2. Kaplan Comprehensive Cancer Center, New York University Medical Center, New York, 10016, NY, USA

    Gabriel Prolla, Roberto Chiarle, Helen Feiner & Giorgio Inghirami

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  1. Jinsong Liu
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  2. Gabriel Prolla
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Liu, J., Prolla, G., Rostagno, A. et al. Initiation of translation from a downstream in-frame AUG codon on BRCA1 can generate the novel isoform protein ΔBRCA1(17aa). Oncogene 19, 2767–2773 (2000). https://doi.org/10.1038/sj.onc.1203599

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