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.