A novel role for the pro-apoptotic protein Noxa in survival and glucose metabolism

Abstract

The studies described in this dissertation focus on a novel mechanism of post-translational control as well as a novel pro-survival role for a canonical tumor-suppressor BH3-only protein, Noxa, in human hematopoietic cells and cancers. An investigation into regulatory mechanisms underlying the constitutive expression of this pro-apoptotic Bcl-2 family member in leukemias, led to the identification of a phosphorylated serine on the protein. The phospho-modification suppressed its pro-apoptotic function and was regulated by glucose levels. Glucose deprivation promoted Noxa dephosphorylation and activated its apoptotic function. The atypical cyclin dependent kinase, Cdk5, was identified as the glucose-sensitive Noxa kinase. Further investigation pointed to a role for phospho-modified Noxa in glucose metabolism; cells over-expressing Noxa increased their uptake of glucose and promoted its utilization in anabolic metabolic pathways that are favored in proliferating cells. Finally, studies showed Noxa and its anti-apoptotic binding partner Mcl-1 associated within cytosolic multi-protein complexes in proliferating T-leukemia and activated primary T-cells. Early characterization and identification of the components point to a novel glucose-responsive signaling role for these complexes. Taken together, these studies offer fresh insights into cancer cell metabolism and the regulation of Bcl-2 proteins and are expected to contribute to novel therapeutic strategies aimed at activating Noxa's pro-apoptotic function in leukemias.