Human insulin receptor substrate-2 (IRS-2) is a primary progesterone response gene

Elevated cAMP has been shown to unmask agonist activity of antiprogestin/an tiglucocorticoid RU486. In our search for cellular target genes induced thr ough this cross-talk mechanism, we identified human insulin receptor substr ate-2 (IRS-2), a cytoplasmic signaling molecule that mediates effects of in sulin, insulin-like growth factor-1 (IGF-I), and other cytokines by acting as a molecular adaptor between diverse receptor tyrosine kinases and downst ream effecters. Our analysis of the regulation of IRS-2 in HeLa cell models shows that synergistic induction of IRS-2 by cAMP and RU486 can be mediate d by progesterone receptors (PR) and glucocorticoid receptors (GR) and occu rs through a relative slow mechanism that requires ongoing protein synthesi s. Importantly, we demonstrate that IRS-2 mRNA is also inducible by progest erone, while glucocorticoid effects are only observed in the presence of cA MP. Up-regulation of IRS-2 by progesterone depends strictly on the presence of PR and occurs through a rapid mechanism, suggesting that it represents a primary transcriptional response. Furthermore, we show that expression of IRS-1, which also binds to receptors of insulin, IGF-I, and cytokines, is unaffected by progesterone. Thus, our results demonstrate that progesterone alters the ratio of IRS-1 and IRS-2 in PR-positive cells and implicate a m echanism through which progesterone can modulate the effects of insulin, IG F-I, and cytokines on cell proliferation, differentiation, and homeostasis.