Rivas Marcos, Santisteban Pilar
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Arturo Duperier # 4, E-28029 Madrid, Spain.
Mol Cell Endocrinol. 2003 Dec 31;213(1):31-45. doi: 10.1016/j.mce.2003.10.029.
Thyrotropin (TSH) is considered the main regulator of thyrocyte differentiation and proliferation. Thus, the characterization of the different signaling pathways triggered by TSH on these cells is of major interest in order to understand the mechanisms implicated in thyroid pathology. In this review we focus on the different signaling pathways involved in TSH-mediated proliferation and their role in thyroid transformation and tumorigenesis. TSH mitogenic activities are mediated largely by cAMP, which in turn may activate protein kinase (PKA)-dependent and independent processes. We analyze the effects of increased cAMP levels and PKA activity during cell cycle progression and the role of this signaling pathway in thyroid tumor initiation. Alternative pathways to PKA in the cAMP-mediated proliferation appear to involve the small GTPases Rap1 and Ras. We analyze the Ras effectors (PI3K, RalGDS and Raf) that are thought to mediate its oncogenic activity, as well as the ability of Ras to induce apoptosis in thyrocytes. Finally, we discuss the activation of the PLC/PKC cascade by TSH in thyroid cells and the role of this signaling pathway in the TSH-mediated proliferation and tumorigenesis.
促甲状腺激素（TSH）被认为是甲状腺细胞分化和增殖的主要调节因子。因此，为了理解甲状腺疾病所涉及的机制，对TSH在这些细胞上触发的不同信号通路进行表征具有重大意义。在本综述中，我们聚焦于TSH介导的增殖所涉及的不同信号通路及其在甲状腺转化和肿瘤发生中的作用。TSH的促有丝分裂活性主要由环磷酸腺苷（cAMP）介导，而cAMP反过来又可能激活依赖蛋白激酶A（PKA）和不依赖PKA的过程。我们分析了细胞周期进程中cAMP水平升高和PKA活性增加的影响，以及该信号通路在甲状腺肿瘤起始中的作用。在cAMP介导的增殖过程中，除PKA之外的替代途径似乎涉及小GTP酶Rap1和Ras。我们分析了被认为介导其致癌活性的Ras效应器（磷脂酰肌醇-3激酶、Ral鸟苷酸解离刺激因子和丝裂原活化蛋白激酶激酶1），以及Ras诱导甲状腺细胞凋亡的能力。最后，我们讨论了TSH在甲状腺细胞中对磷脂酶C/蛋白激酶C级联反应的激活作用，以及该信号通路在TSH介导的增殖和肿瘤发生中的作用。
