Control of Cell Proliferation and Apoptosis by Mob as Tumor Suppressor Protein

Open Access
- Author:
- Wei, Xiaomu
- Graduate Program:
- Genetics
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 21, 2007
- Committee Members:
- Richard W Ordway, Committee Chair/Co-Chair
Zhi Chun Lai, Committee Member
Douglas Cavener, Committee Member
Gong Chen, Committee Member
Wendy Hanna Rose, Committee Member - Keywords:
- hippo
growth inhibition and tumor suppression
Drosophila
mats
warts - Abstract:
- The number of cells in an organism is determined by the number of cells generated as a result of cell proliferation as well the number of cells that are eliminated by cell death. Both cell proliferation and cell death are strictly regulated by developmental mechanism to ensure that an organ of a characteristic shape and size is generated. Mechanisms that regulate normal growth and cell proliferation are often perturbed in cancers. Mutational events found in cancers can either promote growth and cell proliferation or impede cell death. Our laboratory has discovered a novel tumor suppressor in Drosophila that we named mats (Mob as a tumor suppressor) which is capable of regulating both cell proliferation and cell death in a coordinated manner. Loss of Mats function results in increased cell proliferation, impaired apoptosis, and tumor formation characterized by elevated levels of the cell cycle regulator cyclin E and apoptosis inhibitor DIAP1. A human homolog of mats can rescue the lethality associated with loss of Mats function in Drosophila. Importantly, loss-of-function mutation in Mats1 have been identified in a human skin cancer and a mouse breast tumor, suggesting that mammalian mats genes may indeed act as tumor suppressors. The work described here focus on elucidating mechanisms by which Mats protein function as tumor suppressor. I provide biochemical evidence to demonstrate that Mats is a key component in the Hpo-Sav-Wts tumor suppression pathway. Hpo, Mats and Wts interact physically and functionally. Mats phosphorylation by Hpo is critical for Mats to activate Wts kinase. My research objective is to elucidate how exactly these proteins cooperate to form a signaling module, and how they are regulated at a molecular level.