An unliganded thyroid hormone p receptor activates the cyclin D1/cyclin-dependent kinase/retinoblastoma/E2F pathway and induces pituitary tumorigenesis
An unliganded thyroid hormone p receptor activates the cyclin D1/cyclin-dependent kinase/retinoblastoma/E2F pathway and induces pituitary tumorigenesis
复制标题
DOI：
10.1128/mcb.25.1.124-135.2005
复制
发表时间：
2005-01-01
影响因子：
5.3
通讯作者：
Cheng, SY
中科院分区：
文献类型：
--
作者：
Furumoto, H;Ying, H;Cheng, SY
促甲状腺激素（TSH）分泌瘤（TSH-瘤）是组成性分泌TSH的垂体肿瘤。这种异常背后的分子遗传学尚不清楚。我们发现，一个基因敲入小鼠窝藏突变的甲状腺激素受体（TR）β（PV; TR β（PV/PV）小鼠）自发发展TSH瘤。TRbeta（PV/PV）小鼠失去了负反馈调节，TSH水平高度升高，与甲状腺激素水平升高（3，3 '，5-三碘-L-甲状腺原氨酸[T3]）相关。值得注意的是，我们发现所有TRs（TRalpha 1（-/-）TRbeta（-/-））缺陷的小鼠T3和TSH水平相似地增加，但没有明显的TSH瘤，表明垂体-甲状腺轴的失调不足以单独诱导TSH瘤。通过cDNA微阵列比较基因表达谱，发现TRbeta（PV/PV）中细胞周期蛋白D1 mRNA过表达，但TRalpha 1（-/-）TRbeta（-/-）小鼠中没有。仅在TRbeta（PV/PV）小鼠中，细胞周期蛋白D1蛋白的过表达导致细胞周期蛋白D1/细胞周期蛋白依赖性激酶/视网膜母细胞瘤蛋白/E2 F通路的激活。配体TRbeta通过与环AMP反应元件结合蛋白结合而束缚于细胞周期蛋白D1启动子，从而抑制细胞周期蛋白D1的表达。这种抑制作用在突变型PV中丧失，从而导致TRbeta（PV/PV）小鼠中细胞周期蛋白D1的组成性激活。本研究揭示了一种新的分子机制，通过这种机制，一个unliganded TRbeta突变体的行为，以促进垂体肿瘤的发生在体内，并提供了机制的见解，了解患者的TSH瘤的发病机制。
Thyroid-stimulating hormone (TSH)-secreting tumors (TSH-omas) are pituitary tumors that constitutively secrete TSH. The molecular genetics underlying this abnormality are not known. We discovered that a knockin mouse harboring a mutated thyroid hormone receptor (TR) beta (PV; TRbeta(PV/PV) mouse) spontaneously developed TSH-omas. TRbeta(PV/PV) mice lost the negative feedback regulation with highly elevated TSH levels associated with increased thyroid hormone levels (3,3',5-triiodo-L-thyronine [T3]). Remarkably, we found that mice deficient in all TRs (TRalpha1(-/-) TRbeta(-/-)) had similarly increased T3 and TSH levels, but no discernible TSH-omas, indicating that the dysregulation of the pituitary-thyroid axis alone is not sufficient to induce TSH-omas. Comparison of gene expression profiles by cDNA microarrays identified overexpression of cyclin D1 mRNA in TRbeta(PV/PV) but not in TRalpha1(-/-) TRbeta(-/-) mice. Overexpression of cyclin D1 protein led to activation of the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway only in TRbeta(PV/PV) mice. The liganded TRbeta repressed cyclin D1 expression via tethering to the cyclin D1 promoter through binding to the cyclic AMP response element-binding protein. That repression effect was lost in mutant PV, thereby resulting in constitutive activation of cyclin D1 in TRbeta(PV/PV) mice. The present study revealed a novel molecular mechanism by which an unliganded TRbeta mutant acts to contribute to pituitary tumorigenesis in vivo and provided mechanistic insights into the understanding of pathogenesis of TSH-omas in patients.