The growth of solid tumors requires an adequate supply of oxygen and nutrients. Tumor cells tend to proliferate at a rate that exceeds the supply of oxygen and nutrients provided by blood vessels resulting in regions of low oxygen (hypoxia, PO2 =2-15 TORR). Accordingly, tumor cells starved for oxygen activate the transcription factor HIF-1 to stimulate the formation of new blood vessels (angiogenesis). At the molecular level, hypoxia-inducible factor 1 (HIF-1) is the best characterized transcriptional regulator of glycolytic enzymes and VEGF genes. The development of new blood vessels in response to hypoxia is a crucial step in both the growth and metastases of tumors. Although much progress in understanding the biological importance of hypoxic activation of HIF-1 has been made, the fundamental question of the intracellular mechanisms by which cells detect the decrease in oxygen concentration (i.e. oxygen sensing) and initiate signaling pathways that result in hypoxia induced gene transcription remains unanswered. We propose to test the hypothesis that mitochondria serve as oxygen sensors by increasing the generation of reactive oxygen species (ROS) within complex III of the electron transport chain during hypoxia. We hypothesize these ROS serve as signaling molecules to activate the p38a MAPK signaling pathway resulting in HIF-1 dependent tumorigenesis. The degree of hypoxia correlates positively with angiogenesis and metastases, deciphering the intracellular signaling pathways initiated during hypoxia will contribute to our understanding of the basic aspects of tumor progression and to the development of new therapeutic approaches for cancer treatment. ? ? ? ?
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