Loss of the antiproliferative responsiveness to TGF-beta is often considered as a major step in tumor progression. The long-term objective of this application is to understand the molecular basis of how alterations in TGF-beta antiproliferative signaling pathways lead to deregulation of growth control in human diseases. The general strategy of this application is to focus on the ubiquitin and SUMO-1 modifications of tumor suppressor SMAD4 and the physiological functions of these modifications in the regulation of cell growth and tumorigenesis. SMAD4 is a tumor suppressor. It is an essential common mediator for all the SMAD-dependent responses, thus playing a central role in signaling of TGF-beta superfamily. SMAD4 inhibits cell proliferation through transcription-dependent mechanisms. However, the mechanism of how SMAD4 is regulated remains to be elucidated. The unifying hypothesis of this proposal is that the biological functions of SMAD4 are controlled by ubiquitin/proteasome pathway and SUMOylation pathway. To test this hypothesis, we will study the molecular mechanisms of SMAD4 ubiquitination and SUMOylation, their functions in the regulation of TGF-beta signaling, and the physiological outcomes in cell growth regulation in normal and cancer cells.
Four Specific Aims are proposed: 1. Determine the molecular mechanisms for SMAD4-SKP2 interaction, SMAD4 ubiquitination and proteasome-mediated degradation. 2. Examine the effects of SKP2 gene silencing on SMAD4 stability and TGF-beta antiproliferative responses. 3. Investigate the opposing functions of SKP2 and SMAD4 in human cancers. 4. Understand the inter-relationship among ubiquitination, SUMOylation and stability of SMAD4 in human cancers. The proposed studies should help to establish a working theory for the posttranslational regulation of SMAD4 activity during TGF-beta-mediated cell growth control and development, and to understand the mechanisms of SMAD4 actions in malignant transformation and progression of human cancers. Finally, the results may provide a foundation for the rational design of novel therapeutic approaches for disease prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108454-02
Application #
6910805
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Blair, Donald G
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$237,038
Indirect Cost
Name
Baylor College of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Gu, Shuchen; Liu, Yanjing; Zhu, Bowen et al. (2016) Loss of ?-Tubulin Acetylation Is Associated with TGF-?-induced Epithelial-Mesenchymal Transition. J Biol Chem 291:5396-405
Liu, Sisi; Long, Jianyin; Yuan, Bo et al. (2016) SUMO Modification Reverses Inhibitory Effects of Smad Nuclear Interacting Protein-1 in TGF-? Responses. J Biol Chem 291:24418-24430
Wang, G; Yu, Y; Sun, C et al. (2016) STAT3 selectively interacts with Smad3 to antagonize TGF-?. Oncogene 35:4388-98
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Chen, Fenfang; Lin, Xia; Xu, Pinglong et al. (2015) Nuclear Export of Smads by RanBP3L Regulates Bone Morphogenetic Protein Signaling and Mesenchymal Stem Cell Differentiation. Mol Cell Biol 35:1700-11
Chen, Wanze; Wu, Jianfeng; Li, Lisheng et al. (2015) Ppm1b negatively regulates necroptosis through dephosphorylating Rip3. Nat Cell Biol 17:434-44
Zhao, Yulan; Xiao, Mu; Sun, Baoguo et al. (2014) C-terminal domain (CTD) small phosphatase-like 2 modulates the canonical bone morphogenetic protein (BMP) signaling and mesenchymal differentiation via Smad dephosphorylation. J Biol Chem 289:26441-50
Shen, Tao; Sun, Chuang; Zhang, Zhengmao et al. (2014) Specific control of BMP signaling and mesenchymal differentiation by cytoplasmic phosphatase PPM1H. Cell Res 24:727-41

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