Quantitative Modeling and Analysis of the Transforming Growth Factor β Signaling Pathway

被引:45
作者
Chung, Seung-Wook [1 ]
Miles, Fayth L. [2 ,3 ]
Sikes, Robert A. [2 ,3 ]
Cooper, Carlton R. [2 ,3 ]
Farach-Carson, Mary C. [2 ,3 ]
Ogunnaike, Babatunde A. [1 ,3 ]
机构
[1] Univ Delaware, Dept Chem Engn, Newark, DE 19716 USA
[2] Univ Delaware, Dept Biol Sci, Newark, DE 19716 USA
[3] Univ Delaware, Ctr Translat Canc Res, Newark, DE 19716 USA
关键词
TGF-BETA; II RECEPTOR; DEPENDENT DEGRADATION; NUCLEAR-LOCALIZATION; KINETIC-ANALYSIS; SMAD PROTEINS; PROSTATE; DOMAIN; EXPRESSION; CELLS;
D O I
10.1016/j.bpj.2008.11.050
中图分类号
Q6 [生物物理学];
学科分类号
071011 ;
摘要
Transforming growth factor beta (TGF-beta) signaling, which regulates multiple cellular processes including proliferation, apoptosis, and differentiation, plays an important but incompletely understood role in normal and cancerous tissues. For instance, although TGF-beta functions as a tumor suppressor in the premalignant stages of tumorigenesis, paradoxically, it also seems to act as a tumor promoter in advanced cancer leading to metastasis. The mechanisms by which TGF-beta elicits such diverse responses during cancer progression are still not entirely clear. As a first step toward understanding TGF-beta signaling quantitatively, we have developed a comprehensive, dynamic model of the canonical TGF-beta pathway via Smad transcription factors. By describing how an extracellular signal of the TGF-beta ligand is sensed by receptors and transmitted into the nucleus through intracellular Smad proteins, the model provides quantitative insight into how TGF-beta-induced responses are modulated and regulated. Subsequent model analysis shows that mechanisms associated with Smad activation by ligand-activated receptor, nuclear complex formation among Smad proteins, and inactivation of ligand-activated Smad (e.g., degradation, dephosphorylation) may be critical for regulating TGF-beta-targeted functional responses. The model was also used to predict dynamic characteristics of the Smad-mediated pathway in abnormal cells, from which we generated four testable hypotheses regarding potential mechanisms by which TGF-beta's tumor-suppressive roles may appear to morph into tumor-promotion during cancer progression.
引用
收藏
页码:1733 / 1750
页数:18
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