Oxygen, hypoxia-inducible factors, and phosphatidylinositol 3-kinase/Akt signaling in tumor growth and gene expression.

摘要

The HIF and PI3K/Akt pathways are both highly evolutionarily conserved systems which play pivotal roles in the development, growth, and cellular homeostasis of multicellular organisms. Although the HIF system senses and responds to O₂, a central requirement for animal life, and PI3K and Akt respond to the intercellular communication which is not intrinsically necessary for cellular viability, both seem to have evolved to respond to challenges unique to multicellularity. This thesis outlines the ways in which hypoxia and the PI3K/Akt pathway can have both complementary and opposing effects on cell growth, metabolism, and gene expression. Chapter 2 shows that, contrary to existing reports, the PI3K/Akt pathway is neither necessary nor sufficient for HIF regulation. Chapter 3 investigates the parallel but independent effects that HIF-1 and Akt have on tumor growth. Chapter 4 elucidates a novel, HIF-independent hypoxic response regulating the cellular translational control machinery. Finally, Chapter 5 will attempt to place these results in a theoretical framework that addresses some paradoxes regarding the roles of these two pathways in cellular and multicellular life.