Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell proliferation. Yet many cancer cells are resistant to the growth inhibition by TGF-beta while maintaining other aspects of TGF-beta responses that benefit tumor progression. The mechanism for such cell-context dependency in TGF-beta function remains a challenging and important question. Recent studies have suggested that the magnitude and duration of TGF-beta signaling into the nucleus is a critical determinant of the nature of TGF-beta response in the recipient cells. My laboratory is interested in studying the mechanism and regulation of nucleocytoplasmic translocation of Smad proteins, a process that controls the strength and duration of TGF-beta signaling. Modulation of nucleocytoplamic trafficking of Smads is also an important aspect of how TGF-beta signal is interpreted differently by cancer cells. In this proposal, we study regulation of Smad movement that leads to downregulation of TGF-beta signaling into the nucleus. Specifically, we will pursue the following:
Aim#1. TGF-beta-regulated nuclear export of Smad7.
Aim#2. Regulation of Smad trafficking by TGF-beta and mitogenic signals.
Aim#3. Protein Ser/Thr phosphatase against phosphorylated Smad2 (Smad2-P). The outcome of this study will shed light on how the level and duration of TGF-beta signaling into the nucleus is regulated. Identifying key molecules in controlling Smad trafficking will also afford us novel tools to sensitize or desensitize cells to TGF-beta. These regulators of subcellular localization of Smad may serve as potential targets for therapeutic interventions aimed at modulating TGF-beta signaling in treatment of diseases such as cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA108509-03S1
Application #
7264817
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Ogunbiyi, Peter
Project Start
2004-08-01
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$63,643
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Chen, Xiaochu; Xu, Lan (2016) Genome-Wide RNAi Screening to Dissect the TGF-? Signal Transduction Pathway. Methods Mol Biol 1344:365-77
Xu, Lan (2011) Averting a roadblock in transforming growth factor ýý signaling. Mol Cell Biol 31:3684-6
Kaneko, Satoshi; Chen, Xiaochu; Lu, Peiyuan et al. (2011) Smad inhibition by the Ste20 kinase Misshapen. Proc Natl Acad Sci U S A 108:11127-32
Cottonham, Charisa L; Kaneko, Satoshi; Xu, Lan (2010) miR-21 and miR-31 converge on TIAM1 to regulate migration and invasion of colon carcinoma cells. J Biol Chem 285:35293-302
Chen, Xiaochu; Xu, Lan (2010) Specific nucleoporin requirement for Smad nuclear translocation. Mol Cell Biol 30:4022-34
Chen, Shuyi; Kaneko, Satoshi; Ma, Xing et al. (2010) Lissencephaly-1 controls germline stem cell self-renewal through modulating bone morphogenetic protein signaling and niche adhesion. Proc Natl Acad Sci U S A 107:19939-44
Yao, Xiaohao; Chen, Xiaochu; Cottonham, Charisa et al. (2008) Preferential utilization of Imp7/8 in nuclear import of Smads. J Biol Chem 283:22867-74
Xu, Lan; Yao, Xiaohao; Chen, Xiaochu et al. (2007) Msk is required for nuclear import of TGF-{beta}/BMP-activated Smads. J Cell Biol 178:981-94
Xu, Lan (2006) Regulation of Smad activities. Biochim Biophys Acta 1759:503-13
Chen, Hong Bing; Rud, Jonathan G; Lin, Kai et al. (2005) Nuclear targeting of transforming growth factor-beta-activated Smad complexes. J Biol Chem 280:21329-36