Molecular Characterization of Human Homologs of Yeast MOB
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Authors
Chow, Annabelle Tsin Man
Date
2008-09-24T12:30:58Z
Type
thesis
Language
eng
Keyword
Tumor Suppressor , MOB , LATS
Alternative Title
Abstract
MOB (Mps One Binder) is a conserved gene family found in all major kingdoms. The MOB genes are essential components acting in mitotic exit and cytokinesis in both budding and fission yeasts. They are further identified as tumor suppressors in Drosophila (D.) melanogaster. Recently, they are found to be involved in the emerging Drosophila Hippo-LATS tumor suppressor pathway. Seven human homologs of yeast MOB (hMOB1A, 1B, 2A, 2B, 3, 4, 5) have been discovered. The hMOB1B is the gene that has been extensively studied and is reported to be required for the activation of LATS (Large Tumor Suppressor)/NDR (Nuclear Dbf2-related) protein kinase family, however, the functional significance of the gene remains unknown. This study is the first to elucidate the biological and biochemical functions of all seven human MOBs. By examining hMOB mRNA expression in various human tissues, we found that the hMOBs have exhibited different expression patterns. We also investigated the subcellular localization of hMOBs during interphase through immunofluorescent analysis. While hMOB2A is localized in the cytoplasm, hMOB4 is exclusively found in the nucleus. All of the other hMOBs are localized in both cytoplasm and nucleus. Furthermore, we identified hMOB1A and hMOB1B as the main binding partners of LATS and NDR in vitro. Additionally, we successfully identified a region on hMOB1B for the interaction with LATS or NDR and determined the crucial residue that is responsible for the binding of LATS2 with hMOB1B. Most significantly, we found that over-expression of hMOB1B in human cancer cells inhibits cell proliferation and induces cell death. Moreover, hMOB1B when targeted to the plasma membrane dramatically enhances the phenotype. Conversely, small interfering (si) RNA-mediated suppression of either endogenous hMOB1A or hMOB1B causes increased cell proliferation, whereas suppression of both hMOB1A and hMOB1B demonstrates a more significant enhancement in tumor cell growth. Moreover, co-expression of both LATS and hMOB1B targeted to the plasma membrane completely abolishes cell proliferation. Our findings provide convincing evidence that hMOB1A and hMOB1B function as negative regulators of cell proliferation and as pro-apoptotic proteins. Understanding hMOBs functions in the cell and their possible role in tumorigenesis can provide important information for the diagnosis and treatment of human cancers.
Description
Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2008-09-23 14:18:43.896
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