Patyra Konrad, Jaeschke Holger, Löf Christoffer, Jännäri Meeri, Ruohonen Suvi T, Undeutsch Henriette, Khalil Moosa, Kero Andreina, Poutanen Matti, Toppari Jorma, Chen Min, Weinstein Lee S, Paschke Ralf, Kero Jukka
Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.
Turku Center for Disease Modeling, University of Turku, Turku, Finland.
FASEB J. 2018 May 25:fj201800211R. doi: 10.1096/fj.201800211R.
Thyroid function is controlled by thyroid-stimulating hormone (TSH), which binds to its G protein-coupled receptor [thyroid-stimulating hormone receptor (TSHR)] on thyrocytes. TSHR can potentially couple to all G protein families, but it mainly activates the G- and G-mediated signaling cascades. To date, there is a knowledge gap concerning the role of the individual G protein cascades in thyroid pathophysiology. Here, we demonstrate that the thyrocyte-specific deletion of G-protein α subunit (Gα) in adult mice [tamoxifen-inducible G protein α subunit deficient (iTGαKO) mice] rapidly impairs thyrocyte function and leads to hypothyroidism. Consequently, iTGαKO mice show reduced food intake and activity. However, body weight and the amount of white adipose tissue were decreased only in male iTGαKO mice. Unexpectedly, hyperplastic follicles and papillary thyroid cancer-like tumor lesions with increased proliferation and slightly increased phospho-ERK1/2 staining were found in iTGαKO mice at an older age. These tumors developed from nonrecombined thyrocytes still expressing Gα in the presence of highly elevated serum TSH. In summary, we report that partial thyrocyte-specific Gα deletion leads to hypothyroidism but also to tumor development in thyrocytes with remaining Gα expression. Thus, these mice are a novel model to elucidate the pathophysiological consequences of hypothyroidism and TSHR/G/cAMP-mediated tumorigenesis.-Patyra, K., Jaeschke, H., Löf, C., Jännäri, M., Ruohonen, S. T., Undeutsch, H., Khalil, M., Kero, A., Poutanen, M., Toppari, J., Chen, M., Weinstein, L. S., Paschke, R., Kero, J. Partial thyrocyte-specific Gα deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice.
甲状腺功能受促甲状腺激素（TSH）控制，TSH与其在甲状腺细胞上的G蛋白偶联受体[促甲状腺激素受体（TSHR）]结合。TSHR可能与所有G蛋白家族偶联，但主要激活G和G介导的信号级联反应。迄今为止，关于单个G蛋白级联反应在甲状腺病理生理学中的作用存在知识空白。在此，我们证明成年小鼠中甲状腺细胞特异性缺失G蛋白α亚基（Gα）[他莫昔芬诱导的G蛋白α亚基缺陷（iTGαKO）小鼠]会迅速损害甲状腺细胞功能并导致甲状腺功能减退。因此，iTGαKO小鼠的食物摄入量和活动量减少。然而，体重和白色脂肪组织量仅在雄性iTGαKO小鼠中减少。出乎意料的是，在老年iTGαKO小鼠中发现了增生性滤泡和乳头状甲状腺癌样肿瘤病变，其增殖增加且磷酸化ERK1/2染色略有增加。这些肿瘤由在血清TSH高度升高的情况下仍表达Gα的未重组甲状腺细胞发展而来。总之，我们报告部分甲状腺细胞特异性Gα缺失会导致甲状腺功能减退，但也会导致仍表达Gα的甲状腺细胞发生肿瘤。因此，这些小鼠是阐明甲状腺功能减退和TSHR/G/cAMP介导的肿瘤发生的病理生理后果 的新型模型。-帕蒂拉，K.，耶施克，H.，勒夫，C.，扬纳里，M.，鲁奥霍宁，S.T.，温德施，H.，哈利勒，M.，凯罗，A.，波塔宁，M.，托帕里，J.，陈，M.，温斯坦，L.S.，帕施克，R.，凯罗，J. 部分甲状腺细胞特异性Gα缺乏导致小鼠快速发生甲状腺功能减退、增生和乳头状甲状腺癌样病变 。
