Chung Seung-Wook, Miles Fayth L, Sikes Robert A, Cooper Carlton R, Farach-Carson Mary C, Ogunnaike Babatunde A
Department of Chemical Engineering, University of Delaware, Newark, Delaware 19716, USA
Biophys J. 2009 Mar 4;96(5):1733-50. doi: 10.1016/j.bpj.2008.11.050.
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.
转化生长因子β（TGF-β）信号传导可调节包括增殖、凋亡和分化在内的多种细胞过程，在正常组织和癌组织中发挥着重要但尚未完全了解的作用。例如，尽管TGF-β在肿瘤发生的癌前阶段起着肿瘤抑制作用，但矛盾的是，它在导致转移的晚期癌症中似乎也起着肿瘤促进作用。TGF-β在癌症进展过程中引发如此多样反应的机制仍不完全清楚。作为定量理解TGF-β信号传导的第一步，我们通过Smad转录因子建立了一个全面的、动态的经典TGF-β信号通路模型。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，该模型为TGF-β诱导的反应如何被调节和调控提供了定量的见解。随后的模型分析表明，与配体激活受体激活Smad、Smad蛋白之间形成核复合物以及配体激活的Smad失活（如降解、去磷酸化）相关的机制可能对调节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介导的信号通路的动态特征，从中我们提出了四个可测试的假设，涉及TGF-β的肿瘤抑制作用在癌症进展过程中可能转变为肿瘤促进作用的潜在机制。
