A study of the mechanism and method to control the degradation of Mad1 by regulating ubiquitin ligase activity of c-IAP1

Inhibitors of Apoptosis Proteins (IAPs) are known as important regulators of apoptosis. Human X-chromosome-linked IAP (XIAP) directly binds to caspases and inhibits their activities. However, evidence is currently lacking for a role for cellular IAP protein 1 (c-IAP1) in caspase regulation. Up-regulated in many human cancers, c-IAP1 cooperates with c-Myc by an unknown mechanism to promote tumorigenesis in a human live cancer model. Since c-IAP1 is an E3 ubiquitin ligase, we hypothesize that c-IAP1 exerts its oncogenic functions by promoting the ubiquitination and proteasomemediated degradation of certain tumor suppressors. The Myc/Mad/Max transcription factor family contains important regulators of cell proliferation and apoptosis. Onco-protein Myc forms heterodimers with its partner Max to activate gene transcription and cell proliferation, which can be repressed by its antagonist Mad1 (Max-dimerization protein 1) through competing Max. Mad1 has been reported as a tumor suppressor with reduced expression in breast cancers. In the chapter 2 of this dissertation, I present the identification of Mad1 as a substrate of c-IAP1-mediated ubiquitination and proteasomal degradation. The ex