Involvement of the MAP kinase pathways in induction of GADD45 following UVradiation

The p53-regulated stress-inducible gene GADD45 has been shown to participat e in cellular response to DNA damage, including cell cycle checkpoint, apop tosis, and DNA repair. However, the regulation of GADD45 expression is comp lex and may involve both p53-dependent and -independent pathways. Recent fi ndings have demonstrated that the p53-independent induction of GADD45 is ma inly regulated by the transcription factors Oct-l and NF-YA, which directly bind to their consensus motifs located at the GADD45 promoter region. Here , we report that mitogen-activated protein (MAP) kinases are involved in th e induction of the GADD45 promoter after DNA damage. Inhibition of JNK1 and ERK kinase activities either by expression of the dominant negative mutant JNK1 or by treatment with a selective chemical inhibitor of ERK (PD098059) substantially abrogates the UV induction of the GADD45 promoter. In contra st, a p38 kinase inhibitor (SB203580) has little effect on GADD45 induction by UV. In addition, the GADD45 promoter is strongly activated following ex pression of JNKl; Raf-1, which is an upstream activator of the ERK pathway; or MEK1, an upstream activator of both the ERK and the JNK pathways. Activ ation of the GADD45 promoter by MAP kinases does not require normal p53 fun ction. Interestingly, the MAP kinase-regulatory effect appears to be mediat ed via OCT-1 and CAAT motifs since disruption of these sites abrogates acti vation of the GADD45 promoter by MAP kinases. Therefore, these findings ind icate that the MAP kinase pathways are involved in the regulation of the p5 3-independent induction of the GADD45 promoter, probably via interaction wi th transcription factors that directly bind to OCT-1 and CAAT motifs. (C) 2 001 Academic Press.