Mutated in colorectal cancer (MCC) : a novel centrosomal protein involved in intestinal homeostasis and disease

• Main Author: Tomaz, Lucian Brito
• Other Authors: Norris Ray Dunn
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/140724
• Institution: Nanyang Technological University

Mutated in Colorectal Cancer (MCC) is a candidate tumor suppressor gene reported to be somatically mutated in the inherited colorectal cancer (CRC) syndrome Familial Adenomatous Polyposis. Additionally, MCC deletion and loss-of-heterozygosity have also been reported as a common event in human CRC. However, to date, more than 28 years since its discovery, the mechanisms by which MCC contributes to intestinal cancer development as well as its function during normal intestinal tissue homeostasis remain unknown. Here, I investigate the subcellular localization and function of the mouse Mcc homolog in the intestinal epithelium and the consequences of its loss in vivo. My studies reveal that Mcc expression is restricted to cycling cells within intestinal crypts. On a protein level, Mcc specifically localizes to the centrosome of proliferative cells. As cells undergo terminal differentiation, Mcc re-localizes from the centrosome to the apical membrane in enterocytes where it becomes a component of the Non-Centrosomal Microtubules Organizing Center (NMTOC), which is responsible for the establishment of apico-basal polarity and the maintenance of epithelial integrity. Redeployment of proteins from the centrosome to NMTOC sites has been previously reported in other epithelial tissues. However, the molecular mechanisms underlying this redistribution are poorly understood. My biochemical studies establish that phosphorylation of Mcc by Casein Kinases triggers the subcellular redeployment of centrosomal Mcc to the NMTOC. Consistent with a role in the establishment of apico-basal polarity, I additionally provide a comprehensive molecular and morphological characterization of previously unappreciated phenotypes in the adult intestine of Mcc-deficient mice as well as unexpected genetic interactions with the ApcMin intestinal tumor model. Taken together, these findings reveal clinically relevant insights into the involvement of a novel centrosome component in intestinal tissue homeostasis and disease.