c-JUN gene induction and AP-1 activity is regulated by a JNK-dependent pathway in hypoxic HepG2 cells

Hypoxia is an important pathophysiological stress that occurs during blood vessel injuries and tumor growth. It is now well documented that hypoxia le ads to the activation of several transcription factors which participate in the adaptive response of the cells to hypoxia, Among these transcription f actors, AP-1 is rapidly activated by hypoxia and triggers bFGF, VEGF, and t yrosine hydroxylase gene expression, However, the mechanisms of AP-1 activa tion by hypoxia are not well understood. In this report, we studied the eve nts leading to AP-1 activation in hypoxia, We found that c;jun protein accu mulates in hypoxic HepG2 cells. This overexpression is concomitant with c-j un phosphorylation and JNK activation. Moreover, we showed that AP-1 is tra nscriptionally active. We also observed that AP-1 transcriptional activity is inhibited by a MEKK1 dominant negative mutant. Moreover, the MEKK1 domin ant negative mutant as well as deletion of the AP-1 binding sites within th e c-jun promoter inhibited the c-jun promoter activation by hypoxia. All to gether, these results indicate that, in hypoxic HepG2 cells, AP-I is activa ted through a JNK-dependent pathway and that it is involved in the regulati on of the c-jun promoter, inducing a positive feedback loop on AP-1 activat ion via c;jun overexpression, (C) 2001 Academic Press.