REGULATION OF C-JUN EXPRESSION DURING HYPOXIC AND LOW-GLUCOSE STRESS

Hypoxic stress intumorcells hasbeenimplicated inmalignant progression andinthedevelopment of therapeutic resistance. We haveinvestigated theeffects ofacutehypoxic exposure onregulation ofthe proto-oncogene c-jun inSiHacells, a humansquamous carcinoma cell line. Hypoxic exposure produced increased levels ofc-jun mRNA resulting frombothmessage stabilization andtranscriptional activation. A superinduction ofc-jun message resulted during simultaneous oxygen andglucose deprivation, withseveral characteristics ofaninduction mediated byoxidative-stress pathways. Thissuperinduction wasblocked by preincubation ofcells withtheglutathione precursor N-acetyl cysteine orwithphorbol 12-myristate 13-acetate, whichindicates redoxcontrol ofc-jun expression andprobable involvement ofprotein kinase C.Bygel retardation assay, noincrease inAP-1DNA binding activity wasfoundtobeconcomitant withthe transcriptional activation ofc-jun. A lackofincreased DNA binding wasobserved fortheconsensus AP-1 sequence andforthetwoAP-1sequence variants foundwithin thec-Jun promoter. Additionally, hypoxic and low-glucose stress produced noactivation ofstably transfected AP-1reporter sequences. Takentogether, these results indicate that thetranscriptional activation ofc-jun during hypoxic andlow-glucose stress involves redox control andisunlikely tobemediated byAP-1recognition elements within thec-jun promoter.