Hypoxia-induced signaling pathways

The study of tumor hypoxia has advanced in the past decades from the observation that the hypoxic tumor cells which existed furthest from blood vessels were resistant to radiation therapy to the discovery that hypoxia induced signaling pathways and transcription factors that regulated tumor growth, progression, and metastasis. In this dissertation, we explored the role of various cellular effectors in hypoxia-induced signal transduction cascades leading to activation of the specific transcription factor, hypoxia inducible factor-1. We also expanded the understanding of hypoxia by investigating its role in embryonic development. To summarize, we showed that hypoxia and Ha-Ras transformation synergistically led to the activation of vascular endothelial growth factor. We further discovered that hypoxia activated hypoxia inducible factor-1 via a phosphatidylinositol 3-kinase/Akt pathway and that hypoxia also inactivated glycogen synthase kinase-3 via a phosphatidylinositol 3-kinase/Akt-dependent pathway. To answer the fundamental question of how hypoxia is sensed in a cell, we found that hypoxia induced hypoxia inducible factor-1 transcriptional activity through activation of growth factor receptors and a phosphatidylinositol 3-kinase/Akt pathway in a mitochondrial-dependent, reactive oxygen species-dependent, and Src-dependent manner. To study the effect of hypoxia on embryonic development, we collaborated with Dr. Masahiko Fujinaga and found that hypoxia was a normal finding in a developing rat embryos and that hypoxia was essential for proper morphologic development. By learning more about hypoxia-induced signaling pathways and how hypoxia inducible factor-1 is activated and regulated, we are equipped with more potential selective targets for therapeutic intervention against cancer as well as cardiovascular, cerebrovascular, and pulmonary diseases.