Ligand-mediated decrease of thyroid hormone receptor-alpha1 in cardiomyocytes by proteosome-dependent degradation and altered mRNA stability.
Ligand-mediated decrease of thyroid hormone receptor-alpha1 in cardiomyocytes by proteosome-dependent degradation and altered mRNA stability.
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通过蛋白酶体依赖性降解和改变 mRNA 稳定性，配体介导心肌细胞中甲状腺激素受体 α1 的减少。
DOI：
10.1152/ajpheart.00804.2004
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Ojamaa,Kaie
中科院分区：
文献类型：
--
作者：
Kenessey,Agnes;Ojamaa,Kaie
三碘甲腺原氨酸（T3）通过调节许多T3应答基因的转录，对维持正常的心脏收缩功能至关重要。甲状腺激素受体亚型（TRα1，TRβ1）的相对数量和激素利用率决定了T3的有效性。培养的乳鼠心室肌细胞在去T3培养液中主要表达TRα1蛋白，但在T3处理4 h内，TRβ1蛋白显著增加，而TRα1蛋白减少46 ± 5%。利用复制缺陷型腺病毒转染心肌细胞，研究T3介导TRα1蛋白表达减少的机制。蛋白体途径的抑制剂导致泛素化TRα1在细胞核中的积累，并阻止T3诱导的泛素化TRα1的降解，表明T3诱导的蛋白体介导的TRα1的降解;然而，TR泛素化是T3独立的。用瞬时转染甲状腺激素反应元件（TRE）报告质粒测定TRα1的转录活性，结果表明，TRα1的转录活性与T3剂量有关，并与细胞核TRα1含量成反比，10 nM T3的作用最大。定量RT-PCR结果显示，T3处理4 h后，内源性和腺病毒表达的TRα1 mRNA分别下降至54 ± 11和25 ± 5%。在放线菌素D处理的心肌细胞中，TRα1 mRNA半衰期的测量结果显示，T3处理显著降低TRα1 mRNA半衰期，从4 h降至不到2 h，而对TRβ1 mRNA半衰期无影响。这些数据支持蛋白体降解途径和mRNA稳定性改变在T3诱导的心肌细胞核TRα1减少中的作用，并为治疗开发提供了新的细胞靶点。
Tri-iodo-l-thyronine (T3) is essential for maintaining normal cardiac contractile function by regulating transcription of numerous T3-responsive genes. Both hormone availability and relative amounts of nuclear thyroid hormone receptor isoforms (TRα1, TRβ1) determine T3effectiveness. Cultured neonatal rat ventricular myocytes grown in T3-depleted medium expressed predominantly TRα1 protein, but within 4 h of T3treatment, TRβ1 protein increased significantly, whereas TRα1 was decreased by 46 ± 5%. Using replication-defective adenoviruses to overexpress TRα1 in cardiomyocytes, we studied the mechanisms by which T3mediated the decrease in TRα1 protein. Inhibitors of the proteosome pathway resulted in an accumulation of ubiquitylated TRα1 in the nucleus and prevented T3-induced degradation of ubiquitylated TRα1, suggesting that T3induced proteosome-mediated degradation of TRα1; however, TR ubiquitylation was T3independent. TRα1 transcriptional activity, measured using transient transfection of a thyroid hormone-responsive element (TRE) reporter plasmid, was T3dose dependent and inversely proportional to nuclear TRα1 content, with 10 nM T3having maximum effect. Quantitative RT-PCR showed that both endogenous and adenovirus-expressed TRα1 mRNAs were significantly decreased to 54 ± 11 and 25 ± 5%, respectively, within 4 h of T3treatment. Measurements of TRα1 mRNA half-life in actinomycin D-treated cardiomyocytes showed that T3treatment significantly decreased TRα1 mRNA half-life from 4 h to less than 2 h, whereas it had no effect of TRβ1 mRNA half-life. These data support a role for both the proteosome degradation pathway and altered mRNA stability in T3-induced decrease of nuclear TRα1 in the cardiomyocyte and provide novel cellular targets for therapeutic development.
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DOI：
--
发表时间：
1985
期刊：
Journal of Occupational Medicine
影响因子：
--
作者：
R. Lin;P. Dischinger;J. Conde;K. Farrell
通讯作者：
K. Farrell
洛杉矶县男性脑膜瘤的危险因素。
DOI：
--
发表时间：
1983
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
S. Preston‐Martin;M. Yu;B. Henderson;C. Roberts
通讯作者：
C. Roberts
英国病理学家 1974-80 年死亡率研究。
DOI：
10.1136/oem.41.2.188
发表时间：
1984
期刊：
British Journal of Industrial Medicine
影响因子：
--
作者：
J. Harrington;D. Oakes
通讯作者：
D. Oakes
DOI：
--
发表时间：
1986
期刊：
影响因子：
--
作者：
R. Albert;R. Shore;N. Harley;A. Omran
通讯作者：
A. Omran
母亲和女儿的脑膜瘤
影响因子：
9.9
作者：
R. Joynt;G. Perret
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G. Perret