p38 mitogen-activated protein kinase-independent induction of gadd45 expression in nerve growth factor-induced apoptosis in medulloblastomas

We describe a novel nerve growth factor (NGF)signaling pathway leading to g add45 induction that is independent of JNK and p38 MAPK. We used cDNA array s representing 588 genes to investigate the role of differential gene expre ssion in NGF-mediated pleiotropic responses. We compared the gene expressio n profiles obtained from MED283-TrkA cells undergoing NGF-induced apoptosis to PC12 cells undergoing NGF-induced differentiation. An early and specifi c transcriptional target of NGF in MED283-TrkA cells was the DNA-damage-ind ucible gene gadd45. Its magnitude of induction directly correlated with the magnitude of apoptosis in MED283 clones transfected with mutant TrkA recep tors. Although gadd45 has been implicated in stress response signaling, in vitro kinase assays indicated that NGF neither activated c-Jun NH2-terminal kinase (JNK) nor p38 mitogen-activated protein kinase (MAPK). Furthermore, the p38 MAPK inhibitor SB203580 (20 muM) failed to prevent NGF-induced apo ptosis and NGF-induced gadd45 expression. These results suggest that differ ential regulation of gadd45 expression possibly through BRCA1 may be a pote ntial mechanism whereby NGF regulates pleiotropic responses.