Mitogen-activated protein kinases potentiate thyroid hormone receptor transcriptional activity by stabilizing its protein.
Mitogen-activated protein kinases potentiate thyroid hormone receptor transcriptional activity by stabilizing its protein.
复制标题
丝裂原激活的蛋白激酶通过稳定甲状腺激素受体的蛋白质来增强其转录活性。
作者：
Shen;Y. Chang;Yi Hsin Wu;Kwang
甲状腺激素 (T(3)) 对下游基因表达的转录调节是由甲状腺激素受体 (TR) 介导的。 T(3) 结合会诱导复杂的转变，其中 TR 从转录阻遏蛋白转变为转录激活蛋白，并启动下游基因转录。 T(3) 与TR 的结合也会诱导TR 的降解，导致细胞对进一步的T(3) 治疗脱敏。研究表明，TR 的磷酸化对其 T(3) 结合后的活性和稳定性起着关键作用。然而，控制细胞核中 TR 磷酸化的激酶尚未确定。在这项研究中，我们证明 MAPK 可能是负责 TR 核磷酸化的候选者。用特异性抑制剂抑制 MAPK 可抑制 TR 转录活性，并拮抗大卡酸诱导的 TR 转录活性增强。 MAPK 激活剂 MKK6 及其组成型活性突变体 MKK6EE 的过表达显着增加了 TR 活性并保护 TR 免遭降解。还检查了 26S 泛素蛋白酶体在激素结合诱导的 TR 降解中的参与情况。我们发现 MAPK 增强了 TR 的 DNA 结合亲和力。我们的结果表明，MAPK 是负责 TR 核磷酸化的主要激酶，并且是配体结合后调节 TR 转录活性和蛋白质稳定性的关键因素。
Transcriptional regulation of downstream gene expression by thyroid hormone (T(3)) is mediated by the thyroid hormone receptor (TR). T(3) binding induces a complicated transition, where TR converts from a transcriptional repressor into a transcriptional activator and instigates downstream gene transcription. Binding of T(3) to TR also induces the degradation of TR, resulting in desensitization of the cells to further T(3) treatment. It has been shown that phosphorylation of TR plays a critical role in its activity and stability after T(3) binding. However, the kinases in control of phosphorylating TR in the nucleus have not been identified. In this study we demonstrate that MAPKs are possible candidates responsible for the nuclear phosphorylation of TR. Suppression of MAPKs with specific inhibitors repressed TR transcriptional activity and antagonized okadeic acid-induced TR transcriptional activity potentiation. Overexpression of the MAPK activator, MKK6, and its constitutively active mutant, MKK6EE, significantly increased TR activity and protected TR from degradation. Involvement of the 26S ubiquitin proteasome in hormone binding-induced TR degradation was also examined. We found that MAPKs enhanced the DNA binding affinity of TR. Our results suggest that MAPKs are the major kinases responsible for the nuclear phosphorylation of TR and are critical factors modulating the transcriptional activity and protein stability of TR subsequent to ligand binding.
影响因子：
16
作者：
Hammer, GD;Krylova, I;Ingraham, HA
通讯作者：
Ingraham, HA
DOI：
10.1073/pnas.160257997
发表时间：
2000-08-01
影响因子：
11.1
作者：
Dace, A;Zhao, L;Cheng, SY
通讯作者：
Cheng, SY
影响因子：
10.5
作者：
Nagy, L;Kao, HY;Schwabe, JWR
通讯作者：
Schwabe, JWR