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Chair of Endocrinology (S.Sc., A.O., L.L., S.M., A.G., M.A.), Second Faculty of Medicine, Università "La Sapienza" di Roma, Centro Ricerca Ospedale S. Pietro Fatebenefratelli, 00189 Roma, Italy; Department of Experimental Medicine and Pathology (M.Z.), Università "La Sapienza" di Roma, 00161 Roma, Italy; Italian Air Force, Medical Institute (D.D.), 00185 Roma, Italy; Molecular Oncogenesis Laboratory (A.G., S.So.), Regina Elena Cancer Institute, 00162 Roma, Italy; and Department of Clinical Sciences (U.D.M.), Università "La Sapienza" di Roma, 00161 Roma, Italy
Address all correspondence and requests for reprints to: Salvatore Sciacchitano, M.D., Ph.D., Chair of Endocrinology, Universita’ "La Sapienza" di Roma, Department of Experimental Medicine and Pathology, Viale Regina Elena, 324, 00161 Roma. E-mail: salvatore.sciacchitano{at}uniroma1.it.
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.
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