Insulin-like growth factor-I induces bcl-2 promoter through the transcription factor cAMP-response element-binding protein

Insulin-like growth factor-I (IGF-I) is known to prevent apoptosis induced by diverse stimuli. The present study examined the effect of IGF-I on the p romoter activity of bcl-2, a gene with antiapoptotic function, A luciferase reporter driven by the promoter region of bcl-2 from -1640 to -1287 base p airs upstream of the translation start site containing a cAMP-response elem ent was used in transient transfection assays, Treatment of PC12 cells with IGF-I enhanced the bcl-2 promoter activity by 2.3-fold, which was inhibite d significantly (p < 0.01) by SB203580, an inhibitor of p38 mitogen-activat ed protein kinase (MAPK), Cotransfection of the bcl-2 promoter with MAPK ki nase 6 and the beta isozyme of p38 MAPK resulted in 2-3-fold increase in th e reporter activity. The dominant negative form of MAP-KAP-K3, a downstream kinase activated by p38 MAPK, and the dominant negative form of cAMP-respo nse element-binding protein, inhibited the reporter gene activation by IGF- I and p38 beta MAPK significantly (p < 0.01). IGF-I increased the activity of p38 beta MAPK introduced into the cells by adenoviral infection. Thus, w e have characterized a novel signaling pathway (MAPK kinase 6/p38 beta MAPK /MAPKAP-K3) that defines a transcriptional mechanism for the induction of t he antiapoptotic protein Bcl-2 by IGF-I through the nuclear transcription f actor cAMP-response element-binding protein in PC12 cells.