Thyroxine promotes association of mitogen-activated protein kinase and nuclear thyroid hormone receptor (TR) and causes serine phosphorylation of TR
Thyroxine promotes association of mitogen-activated protein kinase and nuclear thyroid hormone receptor (TR) and causes serine phosphorylation of TR
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DOI：
10.1074/jbc.m002560200
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发表时间：
2000-12-01
影响因子：
4.8
通讯作者：
Davis, FB
中科院分区：
文献类型：
--
作者：
Davis, PJ;Shih, A;Davis, FB
非基因组性地由l -甲状腺素（T-4）激活，丝裂原活化蛋白激酶（MAPK）在10-20分钟内与293T细胞核部分的内源性核甲状腺激素受体（TR β 1或TR）络合，导致TR的丝氨酸磷酸化。阻止了T-4诱导的核MAPK-TR共免疫沉淀和TR的丝氨酸磷酸化。T-4治疗导致TR和SMRT（类视黄醛和甲状腺激素受体的沉默介质）的分离，这一作用也被PD 98059抑制，推测是核MAPK与TR相关的结果。将TR基因转染到CV-1细胞中，将TR dna结合域的一个或两个锌指替换为糖皮质激素受体的锌指，将t -4激活的MAPK对TR的磷酸化位点定位在TR dna结合域的第二个锌指的丝氨酸上。在体外无细胞和无激素系统中，纯化的活化MAPK磷酸化重组人TR β 1（102-461）。因此，T-4激活MAPK并导致MAPK介导的TR β 1丝氨酸磷酸化以及TR和共抑制因子SMRT的解离。
Activated nongenomically by L-thyroxine (T-4), mitogen-activated protein kinase (MAPK) complexed in 10-20 min with endogenous nuclear thyroid hormone receptor (TR beta1 or TR) in nuclear fractions of 293T cells, resulting in serine phosphorylation of TR, Treatment of cells with the MAPK kinase inhibitor, PD 98059, prevented both T-4-induced nuclear MAPK-TR co-immunoprecipitation and serine phosphorylation of TR. T-4 treatment caused dissociation of TR and SMRT (silencing mediator of retinoid and thyroid hormone receptor), an effect also inhibited by PD 98059 and presumptively a result of association of nuclear MAPK with TR, Transfection into CV-1 cells of TR gene constructs in which one or both zinc fingers in the TR DNA-binding domain were replaced with those from the glucocorticoid receptor localized the site of TR phosphorylation by T-4-activated MAPK to a serine in the second zinc finger of the TR DNA-binding domain. In an in vitro cell- and hormone-free system, purified activated MAPK phosphorylated recombinant human TR beta1 (102-461). Thus, T-4 activates MAPK and causes MAPK-mediated serine phosphorylation of TR beta1 and dissociation of TR and the co-repressor SMRT.