MECHANISTIC CHARACTERIZATION OF ISM1-MEDIATED INHIBITION OF CANCER

Abstract

Isthmin1 (ISM1) is an endogenous angiogenesis inhibitor identified by our lab that potently triggers apoptosis in endothelial cells (ECs) and tumor cells both in vitro and in vivo. In this thesis, I first demonstrated that knockout of Ism1 gene in mice leads to enhanced subcutaneous B16 melanoma growth. Secondly, I found that the AMOP domain of ISM1 is critical for its internalization and mitochondria trafficking. Correspondingly, AMOP domain alone is capable of inducing EC apoptosis. Thirdly, I determined the regions that are involved in ISM1-GRP78 interaction on ISM1(271-373) and GRP78(101-410) respectively. Lastly, the configurations of GRP78 on mitochondrion and late endosome were investigated via proteinase K digestion, revealing that GRP78 exists as a transmembrane protein in both organelles and also likely on the plasma membrane. Altogether, this work expanded our knowledge of ISM1 protein and its importance and functioning mechanism in angiogenesis and cancer.