V-SRC INDUCES EXPRESSION OF HYPOXIA-INDUCIBLE-FACTOR-1 (HIF-1) AND TRANSCRIPTION OF GENES ENCODING VASCULAR ENDOTHELIAL GROWTH-FACTOR AND ENOLASE-1 - INVOLVEMENT OF HIF-1 IN TUMOR PROGRESSION

Adaptation to hypoxia represents an important aspect of tumor progress ion, Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates essential homeostatic responses to cellular and systemic hyp oxia by activating transcription of multiple genes including those enc oding glycolytic enzymes and vascular endothelial growth factor (VFGF) . In this report, we demonstrate that whereas C-SXC expression is not required for expression of KIF-I or transcriptional activation of gene s encoding VEGF and enolase 1 (ENO1). cells expressing the v-Src oncog ene have increased expression of HiF-1, VEGF, and ENO1 under both hypo xic and nonhypoxic conditions, Expression of V-SRC was associated with increased transcription of reporter genes containing cis-acting hypox ia-response elements from the VEGF and ENO1 genes, and this transcript ional activation required an intact RIF-I binding site. When three rat hepatoma subclones that differed with respect to the level of NIF-I e xpression were injected into nude mice, tumor growth correlated with H IF-1 expression, suggesting that HIF-1 mag be generally involved in tu mor progression, These studies link an oncogene to the induction of HI F-1 expression, thus providing a mechanism for hypoxic adaptation by t umor cells.