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 polypeptide growth factors insulin-like growth factor-I (IGF-I) or epidermal growth factor (EGF), the steroid hormone estradiol (E2) or the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) results in increased steady-state levels of cyclin D1 mRNA and protein. Unexpectedly, this elevation of cyclin D1 expression by all of these agents is inhibited by the specific phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002. Since transcriptional activation of the cyclin D1 promoter by EGF, E2 and TPA is independent of PI3-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 species. In contrast, the stability of the 1.5 kb cyclin D1 mRNA is not affected by PI3-K inhibition. PI3-K-mediated stabilization of mRNA is not a general phenomenon, since other rapidly regulated and unstable mRNAs, such as those encoding c-fos, c-jun and c-myc, are not stabilized upon activation of the PI3-K signaling pathway.
Utrecht Graduate School of Developmental Biology, Laboratory for Physiological Chemistry, Utrecht University, PO Box 80042, 3508 TA Utrecht, The Netherlands.
B
B
Dufourny
van Teeffelen HA
I H
IH
Hamelers
J S
JS
Sussenbach
P H
PH
Steenbergh
D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology*; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D019938:Cyclin D1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004958:Estradiol; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D013755:Tetradecanoylphorbol Acetate