PARENT SESSION
9:00 AM to 11:00 AM
Monday, April 22, 2002
Symposium 10
Molecular Aspects of Hypoxia
Room: Nevada 6-7
Chair: Glazer, Peter¹¹Yale University School of Medicine, New Haven, CT
Speakers: Giaccia, Amato⁴; Laderoute, Keith⁵; Johnson, Randall⁶; Glazer, Peter¹⁴Stanford University School of Medicine, Stanford, CA⁵SRI International, Menlo Park, CA⁶University of California, San Diego, LaJolla, CA¹Yale University School of Medicine, New Haven, CT

(S10-2) Immediate-early Genes and HIF-1: The Example of c-jun .

Laderoute, Keith^*,1, Calaoagan, Joy¹, Knapp, Merrill¹, Johnson, Randall², ¹ Pharmaceutical Discovery Division, Menlo Park, CA² Depart of Biology, La Jolla, CA

ABSTRACT-
Hypoxia (low oxygen tension) is an important physiological stress that contributes to pathologies such as stroke, infarction, and tumorigenesis. We have been investigating the effect of prolonged or chronic hypoxia on expression of the proto-oncogene c-jun and the protein kinase and phosphatase activities that regulate the activity of c-Jun/AP-1 transcription factors. Using genetically manipulated mouse embryonic fibroblasts (mEFs), we have found functional relationships involving c-jun expression and c-Jun phosphorylation and the presence of hypoxia-inducible factor-1 (HIF-1), the oxygen-regulated subunit of the heterodimeric HIF-1 transcription factor (HIF-1-HIF-1/ARNT). Thus, c-jun mRNA expression and c-Jun phosphorylation were found to be completely dependent on the presence of HIF-1 in cells exposed to prolonged hypoxia, but not in cells exposed to less severe stress. More recently, we have been investigating the importance of c-Jun N-terminal sites for HIF-1-dependent c-Jun phosphorylation in hypoxic/anoxic cells. This presentation will describe our current knowledge of hypoxia-inducible c-jun expression and activity, and discuss the response of other immediate-early genes to hypoxia/anoxia. Ultimately, our goal is to understand how immediate-early genes and HIF-1 cooperate to regulate gene expression in the tumor microenvironment.

KEYWORDS: AP-1, HIF-1, immediate-early, phosphorylation