Insulin-like growth factor I-mediated activation of the transcription factor cAMP response element-binding protein in PC12 cells - Involvement of p38mitogen-activated protein kinase-mediated pathway
S. Pugazhenthi et al., Insulin-like growth factor I-mediated activation of the transcription factor cAMP response element-binding protein in PC12 cells - Involvement of p38mitogen-activated protein kinase-mediated pathway, J BIOL CHEM, 274(5), 1999, pp. 2829-2837
IGF-I is known to support growth and to prevent apoptosis in neuronal cells
. Activation of the nuclear transcription factor cAMP response element-bind
ing protein (CREB) has emerged as a central determinant in neuronal functio
ns. In the present investigation, we examined the IGF-I-mediated phosphoryl
ation and transcriptional activation of CREB in rat pheochromocytoma (PC12)
cells, a cellular model for neuronal differentiation, and defined three di
stinct postreceptor signaling pathways important for this effect including
the p38 mitogen-activated protein kinase (MAPK) pathway. CREB phosphorylati
on at serine 133 and its transcriptional activation as measured by a CREB-s
pecific Gal4-CREB reporter and the neuroendocrine-specific gene chromograni
n A was induced 2-3.3-fold by insulinlike growth factor (IGF)-I. This activ
ation was significantly blocked (p < 0.001) by the dominant negative K-CREB
or by mutation of the CRE site. IGF-I stimulated chromogranin A gene expre
ssion by Northern blot analysis 3.7-fold. Inhibition of MAPK kinase with PD
98059, PI 3-kinase with wortmannin, and p38 MAPK with SB203580 blocked IGF-
I-mediated phosphorylation and transcriptional activation of CREB by 30-50%
(p < 0.001), Constitutively active and dominant negative regulators of the
Ras and PI 3-kinase pathways confirmed the contribution of these pathways
for CREB regulation by IGF-I, Cotransfection of PC12 cells with p38 beta an
d constitutively active MAPK kinase 6 resulted in enhanced basal as well. a
s IGF-I-stimulated chromogranin A promoter. IGF-I activated p38 MAPK, which
was blocked by the inhibitor SB203580, This is the first description of a
p38 MAPK-mediated nuclear signaling pathway for IGF-I leading to CREB-depen
dent neuronal specific gene expression.