A dominant negative CREB (cAMP response element-binding protein) isoform inhibits thyrocyte growth, thyroid-specific gene expression, differentiation, and function
A dominant negative CREB (cAMP response element-binding protein) isoform inhibits thyrocyte growth, thyroid-specific gene expression, differentiation, and function
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DOI：
10.1210/me.14.9.1448
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发表时间：
2000-09-01
影响因子：
--
通讯作者：
Jameson, JL
中科院分区：
文献类型：
--
作者：
Nguyen, LQ;Kopp, P;Jameson, JL
cAMP 通过调节甲状腺滤泡细胞增殖、分化和功能来介导 TSH 的作用。为了评估cAMP反应元件结合蛋白（CREB）在体内甲状腺滤泡细胞调节中的功能重要性，我们使用组织特异性启动子将显性失活（DN）CREB亚型的表达靶向转基因小鼠的甲状腺。转基因小鼠表现出严重的生长迟缓和原发性甲状腺功能减退症。血清TSH水平比正常水平高出8倍，而T-4和T-3水平较低。在组织学上，突变的甲状腺的特点是滤泡发育不良，大小不均匀，胶体减少。在转基因甲状腺中观察到纤毛甲状腺上皮细胞，表明滤泡细胞分化失败。与这一假设一致，在半定量 RT-PCR 实验中，DN CREB 转基因抑制了一系列基因的表达，包括甲状腺球蛋白、甲状腺过氧化物酶和 TSH 受体。还观察到甲状腺转录因子 pax-8、TTF-1 和 TTF-2 表达的改变。这些结果表明 CREB 在体内甲状腺生长、分化和功能中发挥着关键作用。
cAMP mediates the effects of TSH by regulating thyroid follicular cell proliferation, differentiation, and function. To assess the functional importance of the cAMP response element binding protein (CREB) in thyroid follicular cell regulation in vivo, we targeted the expression of a dominant negative (DN) CREB isoform to the thyroid glands of transgenic mice using a tissue-specific promoter. Transgenic mice exhibited severe growth retardation and primary hypothyroidism. Serum levels of TSH were elevated 8-fold above normal levels, and T-4 and T-3 levels were low. Histologically, the mutant thyroid glands were characterized by poorly developed follicles that were heterogeneous in size with diminished colloid. Ciliated thyroid epithelial cells were observed in the transgenic thyroid glands, suggesting a failure of follicular cell differentiation. Consistent with this hypothesis, the DN CREB transgene inhibited the expression of an array of genes including thyroglobulin, thyroperoxidase, and the TSH receptor in semiquantitative RT-PCR experiments. Altered expression of the thyroid transcription factors pax-8, TTF-1, and TTF-2 was also observed. These results demonstrate a critical role for CREB in thyroid growth, differentiation, and function in vivo.