The pituitary hormone prolactin (PRL) stimulates the growth and differentiation of many tissues and cell types. To understand a role of PRL in mitogenic signaling, we isolated a number of immediate early genes activated after PRL stimulation. One such gene, NudC, was cloned as an early growth response gene. Genetic, biochemical and cellular studies show that NudC associates with the microtubule (MT)-dependent dynein/dynactin motor complex that mediates many mitotic processes. Our studies suggest that NudC plays multiple roles in mitosis (nuclear division) and cytokinesis (cytoplasmic division). We showed that altering NudC levels by either small interference RNA (siRNA)-mediated gene silencing or adenovirus-mediated overexpression resulted in defects in cytokinesis, as reflected by an increase in the number of multinucleated cells and cells with persistent intercellular connections. MTs in the midzone and midbody matrix appeared disorganized, providing a possible clue on a cytokinesis defect. In addition, we show that NudC is a mitotic phosphoprotein and it interacts with the mitotic kinase polo-like kinase 1 (Plkl), suggesting that NudC phosphorylation may affect NudC functions during mitosis. We hypothesize that a precise level and phosphorylation state of NudC are required for mitotic progression and completion of cytokinesis, and that NudC functions by regulating the dynein/dynactin complex and MT dynamics during mitosis and cytokinesis. To delineate NudC functions in mitogenic signaling, we propose to 1) Determine NudC function in mitosis and cytokinesis by analyzing how changes in NudC levels and phosphorylation state affect mitosis progression and completion of cytokinesis, and to 2) Analyze regulation of dynein/dynactin by NudC by addressing how NudC regulates dynein complex stability and MT dynamics. These studies should contribute to a fundamental understanding of the mechanisms of PRL-mediated mitogenic signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053176-08
Application #
7212071
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Malozowski, Saul N
Project Start
1998-03-15
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2010-03-31
Support Year
8
Fiscal Year
2007
Total Cost
$326,244
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Chuang, Carol; Pan, Jing; Hawke, David H et al. (2013) NudC deacetylation regulates mitotic progression. PLoS One 8:e73841
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Kurasawa, Yasuhiro; Yu-Lee, Li-yuan (2010) PICH and cotargeted Plk1 coordinately maintain prometaphase chromosome arm architecture. Mol Biol Cell 21:1188-99

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