Eukaryotic cells must temporally coordinate diverse cellular processes to ensure the fidelity of cell proliferation. Defects in the execution or temporal coordination of cell cycle processes increase genetic instability and promote cancer. Thus, it is important to resolve the mechanisms of conserved cell cycle regulations. The Saccharomyces cerevisiae Mitotic Exit Network (MEN) is essential for coordinating several cell cycle processes during mitotic exit, including cyclin dependent kinase (CDK) inactivation, cytokinesis, mitotic spindle disassembly and activation of G1 gene expression. The Mob1-Dbf2 kinase complex is a key component of MEN and is orthologous to the human Mob1A-LATS kinase complex, which functions as mammalian tumor suppressor. Yeast Mob1-Dbf2 has been implicated in cytokinesis, activation of Cdc14 phosphatase (which enables mitotic exit by inactivating CDK phosphorylations) and mitotic spindle function via regulation of Aurora kinase. Nevertheless, the functional mechanisms and substrates of yeast and mammalian Mob1-Dbf2 kinases are not known. The goal of the proposed work is to determine how the Mob1-Dbf2 kinase complex temporally coordinates cytokinesis with mitotic exit and chromosome segregation. We propose three aims.
The first aim i s to determine the role of Mob1-Dbf2 in cytokinesis. We will conduct cell biological, biochemical and genetic approaches to test the hypothesis that MEN controls cytokinesis by regulating targeted membrane deposition and by activating the RAM (Regulation of Ace2 transcription factor and polarized Morphogenesis) signaling network, which controls cytokinesis, gene expression and other functions.
The second aim i s to determine the role of the Mob1-Dbf2 kinase complex in Cdc14 phosphatase activation during mitotic exit and cytokinesis. We will test the hypothesis that Mob1- Dbf2 kinase directly induces Cdc14 phosphatase release from the nucleolus and will define the epistatic relationship of Mob1-Dbf2 and Cdclp with respect to cytokinesis.
The third aim i s to determine the role of Mob1-Dbf2 in mitotic checkpoint signaling. We will test the hypothesis that Mob1-Dbf2 is required for Aurora-dependent checkpoint signaling. Given the conservation of Mob1-Dbf2, the proposed work will help resolve the function of all MEN-related signaling networks, including the human hMob1A-LATS1 tumor suppressor pathway, and will help elucidate the underlying mechanisms of cancer development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060575-07
Application #
7337616
Study Section
Nuclear Dynamics and Transport (NDT)
Program Officer
Zatz, Marion M
Project Start
2000-08-01
Project End
2010-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
7
Fiscal Year
2008
Total Cost
$315,000
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kurischko, Cornelia; Kim, Hong Kyung; Kuravi, Venkata K et al. (2011) The yeast Cbk1 kinase regulates mRNA localization via the mRNA-binding protein Ssd1. J Cell Biol 192:583-98
Kuravi, Venkata K; Kurischko, Cornelia; Puri, Manasi et al. (2011) Cbk1 kinase and Bck2 control MAP kinase activation and inactivation during heat shock. Mol Biol Cell 22:4892-907
Kurischko, Cornelia; Kuravi, Venkata K; Herbert, Christopher J et al. (2011) Nucleocytoplasmic shuttling of Ssd1 defines the destiny of its bound mRNAs. Mol Microbiol 81:831-49
Kurischko, Cornelia; Kuravi, Venkata K; Wannissorn, Nattha et al. (2008) The yeast LATS/Ndr kinase Cbk1 regulates growth via Golgi-dependent glycosylation and secretion. Mol Biol Cell 19:5559-78
Bembenek, Joshua; Kang, Jungseog; Kurischko, Cornelia et al. (2005) Crm1-mediated nuclear export of Cdc14 is required for the completion of cytokinesis in budding yeast. Cell Cycle 4:961-71
Bothos, John; Tuttle, Robyn L; Ottey, Michelle et al. (2005) Human LATS1 is a mitotic exit network kinase. Cancer Res 65:6568-75
Stoepel, Jan; Ottey, Michelle A; Kurischko, Cornelia et al. (2005) The mitotic exit network Mob1p-Dbf2p kinase complex localizes to the nucleus and regulates passenger protein localization. Mol Biol Cell 16:5465-79
Kurischko, Cornelia; Weiss, Gretchen; Ottey, Michelle et al. (2005) A role for the Saccharomyces cerevisiae regulation of Ace2 and polarized morphogenesis signaling network in cell integrity. Genetics 171:443-55
Stavridi, Elena S; Harris, Kimberly G; Huyen, Yentram et al. (2003) Crystal structure of a human Mob1 protein: toward understanding Mob-regulated cell cycle pathways. Structure 11:1163-70
Nelson, Bryce; Kurischko, Cornelia; Horecka, Joe et al. (2003) RAM: a conserved signaling network that regulates Ace2p transcriptional activity and polarized morphogenesis. Mol Biol Cell 14:3782-803

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