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Horm Metab Res 2003; 35(11/12): 758-762
DOI: 10.1055/s-2004-814154
Original
© Georg Thieme Verlag Stuttgart · New York

Functional and Physical Interactions between BRCA1 and p53 in Transcriptional Regulation of the IGF-IR Gene

S.  Abramovitch1 , H.  Werner1
  • 1 Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel
Further Information

Publication History

Received 28 August 2003

Accepted after Revision 8 October 2003

Publication Date:
07 January 2004 (online)

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Abstract

The insulin-like growth factor-I receptor (IGF-IR) mediates the biological actions of the IGFs, and is critical for normal mammary gland development as well as for malignant transformation. Transcription of the IGF-IR gene is under inhibitory control by a number of transcription factors with tumor suppressor activity, including BRCA1 and p53. To assess the potential functional interactions between BRCA1 and p53 in transcriptional control of the IGF-IR gene, co-transfections were performed on MCF-7 breast cancer cells using an IGF-IR promoter luciferase reporter construct together with expression vectors encoding BRCA1 and wild-type and mutant p53. Similar experiments were performed in the colorectal cancer cell line HCT116+/+, which expresses a wild-type p53 gene, and its HCT116-/- derivative, which lacks p53. BRCA1 was able to suppress IGF-IR promoter activity both in the absence and presence of p53. However, BRCA1 had no effect in mutant p53-expressing cells. Co-immunoprecipitation experiments showed that BRCA1 and p53 physically interact. In summary, our data suggest that the transcriptional activity of BRCA1 depends on the cellular status of p53. Inability of mutant tumor suppressors to repress IGF-IR gene expression may result in increased IGF-IR levels and IGF binding, leading to a reduction in apoptosis and enhanced survival capacity of malignant cells.

Key words

IGF - Receptor - Gene expression - Promoter - Transcription factors - Breast cancer

References

  • 1 Yee D, Paik S, Lebovic G S, Marcus R R, Favoni R E, Cullen K J, Lippman M E, Rosen N. Analysis of insulin-like growth factor I gene expression in malignancy: evidence for a paracrine role in human breast cancer.  Mol Endocrinol. 1989;  3 509-514
    PubMedGoogle Scholar
  • 2 Surmacz E. Function of the IGF-I receptor in breast cancer.  J Mammary Gland Biol Neoplasia. 2000;  5 95-105
    CrossrefPubMedGoogle Scholar
  • 3 Osborne C K, Clemmons D R, Arteaga C L. Regulation of breast cancer growth by insulin-like growth factors.  J Steroid Biochem Mol Biol. 1990;  37 805-809
    CrossrefPubMedGoogle Scholar
  • 4 Hankinson S E, Willett W C, Colditz G A, Hunter D J, Michaud D S, Deroo B, Rosner B, Speizer F E, Pollak M. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer.  The Lancet. 1998;  351 1393-1396
    CrossrefPubMedGoogle Scholar
  • 5 Happerfield L C, Miles D W, Barnes D M, Thomsen L L, Smith P, Hanby A M. The localization of the insulin-like growth factor receptor 1 (IGFR-1) in benign and malignant breast tissue.  J Pathol. 1997;  183 412-417
    PubMedGoogle Scholar
  • 6 Turner B C, Haffty B G, Narayanan L, Yuan J, Havre P A, Gumbs A A, Kaplan L, Burgaud J-L, Carter D, Baserga R, Glazer P M. Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation.  Cancer Res. 1997;  57 3079-3083
    PubMedGoogle Scholar
  • 7 Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J, Mayer D. Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer.  Int J Cancer. 2000;  89 506-513
    CrossrefPubMedGoogle Scholar
  • 8 Pennisi P A, Barr V, Nunez N P, Stannard B, LeRoith D. Reduced expression of insulin-like growth factor I receptors in MCF-7 breast cancer cells leads to a more metastatic phenotype.  Cancer Res. 2002;  62 6529-6537
    PubMedGoogle Scholar
  • 9 Werner H, Roberts C T Jr. The IGF-I receptor gene: a molecular target for disrupted transcription factors.  Genes Chromosomes Cancer. 2003;  36 113-120
    CrossrefPubMedGoogle Scholar
  • 10 Werner H, Bach M A, Stannard B, Roberts C T Jr, LeRoith D. Structural and functional analysis of the insulin-like growth factor I receptor gene promoter.  Mol Endocrinol. 1992;  6 1545-1558
    CrossrefPubMedGoogle Scholar
  • 11 Maor S B, Abramovitch S, Erdos M R, Brody L C, Werner H. BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1.  Mol Gen Metab. 2000;  69 130-136
    PubMedGoogle Scholar
  • 12 Abramovitch S, Glaser T, Ouchi T, Werner H. BRCA1-Sp1 interactions in transcriptional regulation of the IGF-IR gene.  FEBS Lett. 2003;  541 149-154
    CrossrefPubMedGoogle Scholar
  • 13 Miki Y, Swensen J, Shattuck-Eidens D, Futreal P A, Harshman K, Tavtigian S, Liu Q. et al . A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.  Science. 1994;  266 66-71
    CrossrefPubMedGoogle Scholar
  • 14 Futreal P A, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, Bennett L M. et al . BRCA1 mutations in primary breast and ovarian carcinomas.  Science. 1994;  266 120-122
    PubMedGoogle Scholar
  • 15 Wang Q, Zhang H, Fishel R, Greene M I. BRCA1 and cell signaling.  Oncogene. 2000;  19 6152-6158
    CrossrefPubMedGoogle Scholar
  • 16 Werner H, Karnieli E, Rauscher F J III, LeRoith D. Wild type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene.  Proc Natl Acad Sci USA. 1996;  93 8318-8323
    CrossrefPubMedGoogle Scholar
  • 17 Zhang H, Somasundaram K, Peng Y, Tian H, Zhang H, Bi D, Weber B L, El-Deiry W S. BRCA1 physically associates with p53 and stimulates its transcriptional activity.  Oncogene. 1998;  16 1713-1721
    CrossrefPubMedGoogle Scholar
  • 18 Ouchi T, Monteiro A NA, August A, Aaronson S A, Hanafusa H. BRCA1 regulates p53-dependent gene expression.  Proc Natl Acad Sci USA. 1998;  95 2302-2306
    CrossrefPubMedGoogle Scholar
  • 19 Ludwig T, Chapman D L, Papaioannou V E, Efstratiadis A. Targeted mutation of breast cancer susceptibility gene homologs in mice: lethal phenotypes Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos.  Genes Dev. 1997;  11 1226-1241
    PubMedGoogle Scholar
  • 20 Sourvinos G, Spandidos D A. Decreased BRCA1 expression levels may arrest the cell cycle through activation of p53 checkpoint in human sporadic breast tumors.  Biochem Biophys Res Comm. 1998;  245 75-80
    CrossrefPubMedGoogle Scholar
  • 21 Arizti P, Fang L, Park I, Yin Y, Solomon E, Ouchi T, Aaronson S A, Lee S W. Tumor suppressor p53 is required to modulate BRCA1 expression.  Mol Cell Biol. 2000;  20 7450-7459
    CrossrefPubMedGoogle Scholar
  • 22 Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown J P, Sedivy J M, Kinzler K W, Vogelstein B. Requirement for p53 and p21 to sustain G2 arrest after DNA damage.  Science. 1998;  282 1497-1501
    CrossrefPubMedGoogle Scholar
  • 23 Werner H, Rauscher F J III, Sukhatme V P, Drummond I A, Roberts C T Jr, LeRoith D. Transcriptional repression of the insulin-like growth factor I receptor (IGF-I-R) gene by the tumor suppressor WT1 involves binding to sequences both upstream and downstream of the IGF-I-R gene transcription start site.  J Biol Chem. 1994;  269 12 577-12 582
    PubMedGoogle Scholar
  • 24 Idelman G, Glaser T, Roberts C T Jr, Werner H. WT1-p53 interactions in IGF-I receptor gene regulation.  J Biol Chem. 2003;  278 3474-3482
    CrossrefPubMedGoogle Scholar
  • 25 Oren M. p53: The ultimate tumor suppressor gene?.  FASEB J. 1992;  6 3169-3176
    PubMedGoogle Scholar
  • 26 Chen Y, Chen C-F, Riley D J, Allred D C, Chen P-L, von Hoff D, Osborne C K, Lee W-H. Aberrant subcellular localization of BRCA1 in breast cancer.  Science. 1995;  270 789-791
    PubMedGoogle Scholar
  • 27 Castilla L H, Couch F J, Erdos M R, Hoskins K F, Calzone K, Garber J E, Boyd J, Lubin M B, Deshano M L, Brody L C. et al . Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.  Nature Gen. 1994;  8 387-391
    PubMedGoogle Scholar
  • 28 Deng C X, Brodie S G. Roles of BRCA1 and its interacting proteins.  BioEssays. 2000;  22 28-737
    PubMedGoogle Scholar
  • 29 Hohenstein P, Giles R H. BRCA1: a scaffold for p53 response?.  Trends Gen. 2003;  19 89-494
    PubMedGoogle Scholar
  • 30 Gallaher B W, Hille R, Raile K, Kiess W. Apoptosis: live or die - hard work either way!.  Horm Metab Res. 2001;  33 11-519
    PubMedGoogle Scholar

H. Werner, Ph. D. 

Department of Clinical Biochemistry, Sackler School of Medicine

Tel Aviv University · Tel Aviv 69978 · Israel

Phone: +972(3)6408542

Fax: +972(3)6406087

Email: hwerner@post.tau.ac.il