Reciprocal negative regulation between thyrotropin/3′,5′-cyclic adenosine monophosphate-mediated proliferation and caveolin-1 expression in human and murine thyrocytes
Reciprocal negative regulation between thyrotropin/3′,5′-cyclic adenosine monophosphate-mediated proliferation and caveolin-1 expression in human and murine thyrocytes
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DOI：
10.1210/me.2006-0328
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发表时间：
2007-04-01
影响因子：
--
通讯作者：
Van Sande, Jacqueline
中科院分区：
文献类型：
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作者：
Costa, Maria Jose;Senou, Maximin;Van Sande, Jacqueline
小窝蛋白的表达在人甲状腺自主性腺瘤的组织样品和该疾病的动物模型中下调。由于存在于甲状腺中的几种细胞类型表达小窝蛋白，因此尚不清楚这种下调是否发生在甲状腺细胞中，以及这种下调在肿瘤背景下的机制和作用。在这里，我们表明，TSH/cAMP/cAMP依赖性蛋白激酶的长时间刺激分离的人甲状腺细胞抑制小窝蛋白的表达。小窝蛋白的表达不会受到与甲状腺生长/功能相关的其他信号通路激活剂的下调。因此，自主性腺瘤中小窝蛋白表达的下调是甲状腺细胞中TSH/cAMP通路慢性激活的直接结果。小窝蛋白-1的下调发生在mRNA水平，随之而来的是蛋白质的减少。TSH/cAMP诱导小窝蛋白-1 mRNA的转录依赖性、非依赖性的不稳定。这种效应与甲状腺细胞中该级联的已知增殖作用相关。在体内，小窝蛋白-1敲除小鼠的甲状腺细胞显示出增强的增殖。这第一次证明了通过一个促有丝分裂级联反应特异性小窝蛋白-1下调的体内意义及其与人类疾病的关系。
The expression of caveolins is down-regulated in tissue samples of human thyroid autonomous adenomas and in the animal model of this disease. Because several cell types present in thyroid express caveolins, it remained unclear if this down-regulation occurs in thyrocytes and which are the mechanism and role of this down-regulation in the tumor context. Here we show that prolonged stimulation of isolated human thyrocytes by TSH/cAMP/cAMP-dependent protein kinase inhibits caveolins' expression. The expression of caveolins is not down-regulated by activators of other signaling pathways relevant to thyroid growth/function. Therefore, the down-regulation of caveolins' expression in autonomous adenomas is a direct consequence of the chronic activation of the TSH/cAMP pathway in thyrocytes. The down-regulation of caveolin-1 occurs at the mRNA level, with a consequent protein decrease. TSH/cAMP induces a transcription-dependent, translation-independent destabilization of the caveolin-1 mRNA. This effect is correlated to the known proliferative role of that cascade in thyrocytes. In vivo, thyrocytes of caveolin-1 knockout mice display enhanced proliferation. This demonstrates, for the first time, the in vivo significance of the specific caveolin-1 down-regulation by one mitogenic cascade and its relation to a human disease.