TUMOR HYPOXIA AND C JUN PROTOONCOGENE EXPRESSION

Sri International, Menlo Park CA

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Abstract

DESCRIPTION: Deficiencies in blood supply in tumors lead to suboptimal concentrations ox oxygen, glucose, and other substances. Tumor hypoxia is a patho-physiological stress that contributes to clinically important phenomena such as resistance to radio-therapy. Preliminary data is presented that hypoxia and reoxygention stimulate expression of the c-jun pronto-oncogene and c-jun/AP1 transcriptional complexes. Studies are proposed to identify the stress-inducible biochemical pathways that activate c-jun expression and transform cells in response to hypoxia and reoxygenation. In addition, the physiologic consequences of this activation will be investigated, with a particular focus on activation of the tyrosine phosphatase gene, MKP-1, and activation of the matrix metalloproteinase gene MMP-2/GL-1. Genes such as these regulated by the c- jun/AP1 complexes may be part of a concerted response to injury or environmental stress associated with perturbations of cellular redox states.