Cloning of the mouse insulin receptor substrate-3 (mIRS-3) promoter, and its regulation by p53

Salvatore Sciacchitano, Andrea Orecchio, Luca Lavra, Silvia Misiti, Anna Giacchini, Massimo Zani, Daniele Danese, Aymone Gurtner, Silvia Soddu, Umberto Di Mario, Mario Andreoli

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The insulin receptor susbtrate-3 (IRS-3) is a member of a family of intermediate adapter proteins that function as major intracellular targets for phosphorylation by the activated insulin and IGF-I receptors. Among the four IRS proteins identified so far, IRS-3 exhibits a rather peculiar expression pattern during both the embryonic development and adult life, suggesting a different mechanism of regulation of its expression. In this study, we cloned the 5′ flanking region of the mIRS-3 gene and analyzed its promoter activity. The mIRS-3 promoter is inhibited by wild-type p53, and this effect is completely abolished by cotransfection of a dominant negative p53. Tumor-derived p53 mutants show variable, but lower suppressing capability than wt p53. In addition, treatment with doxorubicin inhibits endogenous expression of mIRS-3 mRNA in C2C12 and 3T3-L1 cells. The DNA region spanning from nucleotides -287 and -178 in the mIRS-3 promoter is responsible for a 32.2% reduction of the mouse double minute 2 (MDM2) promoter activity, suggesting its involvement in the p53-mediated inhibitory effect. In conclusion, our study demonstrates that the mIRS-3 promoter is regulated by p53 at the transcriptional level. The inhibition of mIRS-3 promoter by wild-type p53, and its de-repression by tumor-derived p53 mutants, appears to be similar to that previously reported for the IGF-I receptor promoter, suggesting a common role of these two genes in p53-mediated cell growth and differentiation.

Original languageEnglish
Pages (from-to)1577-1589
Number of pages13
JournalMolecular Endocrinology
Issue number7
Publication statusPublished - 2002

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

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    Sciacchitano, S., Orecchio, A., Lavra, L., Misiti, S., Giacchini, A., Zani, M., Danese, D., Gurtner, A., Soddu, S., Mario, U. D., & Andreoli, M. (2002). Cloning of the mouse insulin receptor substrate-3 (mIRS-3) promoter, and its regulation by p53. Molecular Endocrinology, 16(7), 1577-1589.