| First Author | Sciacchitano S | Year | 2002 |
| Journal | Mol Endocrinol | Volume | 16 |
| Issue | 7 | Pages | 1577-89 |
| PubMed ID | 12089352 | Mgi Jnum | J:77749 |
| Mgi Id | MGI:2182514 | Doi | 10.1210/mend.16.7.0881 |
| Citation | Sciacchitano S, et al. (2002) Cloning of the Mouse Insulin Receptor Substrate-3 (mIRS-3) Promoter, and Its Regulation by p53. Mol Endocrinol 16(7):1577-89 |
| abstractText | 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. |
