Stabilization of cyclin D1 mRNA via the phosphatidylinositol 3-kinase pathway in MCF-7 human breast cancer cells

Treatment of quiescent MCF-7 human breast cancer cells with either the poly peptide growth factors insulin-like growth factor-I (IGF-I) or epidermal gr owth factor (EGF), the steroid hormone estradiol (E2) or the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) results in increased steady-stat e levels of cyclin D1 mRNA and protein. Unexpectedly, this elevation of cyc lin D1 expression by all of these agents is inhibited by the specific phosp hatidylinositol 3-kinase (PI3-K) inhibitor LY294002. Since transcriptional activation of the cyclin D1 promoter by EGF, E2 and TPA is independent of P U-K activity, these findings suggest a post-transcriptional role for PI3-K in the regulation of cyclin D1 expression. Here we show that inhibition of PI3-K by LY294002 decreases the half-life of the 4.5 kb cyclin D1 mRNA spec ies. In contrast, the stability of the 1.5 kb cyclin D1 mRNA is not affecte d by PI3-K inhibition. PI3-K-mediated stabilization of mRNA is not a genera l phenomenon, since other rapidly regulated and unstable mRNAs, such as tho se encoding c-fos, c-jun and c-myc, are not stabilized upon activation of t he PI3-K signaling pathway.