Quantitative Modeling and Analysis of the Transforming Growth Factor β Signaling Pathway
Quantitative Modeling and Analysis of the Transforming Growth Factor β Signaling Pathway
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DOI：
10.1016/j.bpj.2008.11.050
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发表时间：
2009-03-04
影响因子：
3.4
通讯作者：
Ogunnaike, Babatunde A.
中科院分区：
文献类型：
--
作者：
Chung, Seung-Wook;Miles, Fayth L.;Ogunnaike, Babatunde A.
转化生长因子β（TGF-β）信号传导调节多个细胞过程，包括增殖、凋亡和分化，在正常和癌组织中起重要但不完全理解的作用。例如，虽然TGF-β在肿瘤发生的癌前阶段作为肿瘤抑制因子发挥作用，但矛盾的是，它似乎也在导致转移的晚期癌症中作为肿瘤促进因子发挥作用。TGF-β在癌症进展过程中引起这种不同反应的机制仍然不完全清楚。作为定量理解TGF-β信号传导的第一步，我们已经开发了一个全面的，动态的模型，通过Smad转录因子的经典TGF-β途径。通过描述TGF-β配体的细胞外信号如何被受体感知并通过细胞内Smad蛋白传递到细胞核中，该模型提供了对TGF-β诱导的反应如何被调制和调节的定量见解。随后的模型分析表明，与配体激活的受体激活Smad、Smad蛋白之间的核复合物形成以及配体激活的Smad的失活（例如，降解、去磷酸化）可能对于调节TGF-β靶向的功能反应至关重要。该模型还用于预测异常细胞中Smad介导的途径的动态特征，从中我们产生了四个关于TGF-β的肿瘤抑制作用可能在癌症进展期间演变为肿瘤促进的潜在机制的可检验假设。
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.