cAMP-Dependent Posttranscriptional Regulation of Steroidogenic Acute Regulatory (STAR) Protein by the Zinc Finger Protein ZFP36L1/TIS11b
cAMP-Dependent Posttranscriptional Regulation of Steroidogenic Acute Regulatory (STAR) Protein by the Zinc Finger Protein ZFP36L1/TIS11b
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DOI：
10.1210/me.2008-0296
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发表时间：
2009-04-01
影响因子：
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通讯作者：
Jefcoate, Colin
中科院分区：
文献类型：
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作者：
Duan, Haichuan;Cherradi, Nadia;Jefcoate, Colin
Star在类固醇生成细胞中以3.5 kb和1.6 kb转录本表达，仅在其3'-非翻译区（3'- utr）中有所不同。在小鼠MA10睾丸和Y-1肾上腺系中，Br-cAMP优先刺激3.5 kb mRNA。ACTH在原代牛肾上腺皮质细胞中同样具有选择性。3.5 kb的形式在延伸的3'-UTR中含有富au元素（AURE），这促进了周转率。在3.5 kb mRNA的峰值刺激后，可以看到降解。锌指蛋白ZFP36L1/TIS11b与延伸的3'-UTR中的UAUUUAUU重复序列结合，可增强Star mRNA的周转。TIS11b在每种细胞类型中与Star mRNA并行被快速刺激。TIS11b的共转染选择性地降低巨细胞病毒促进的Star mRNA和含有延长的3'-UTR的荧光素酶-Star 3'-UTR报告基因。在TIS11b与3.5 kb星的延伸3'-UTR之间证明了直接复杂的形成。AURE突变表明，tis11b介导的不稳定需要前两个UAUUUAUU基序。同时结合AURE的HuR不影响Star的表达。靶向小干扰RNA敲低TIS11b特异性地增强了牛肾上腺皮质细胞、MA-10和Y-1细胞中3.5 kb Star mRNA的刺激，但不影响峰值刺激后的逆转。直接转染Star mRNA表明，Br-cAMP刺激了独立于AURE的3.5 kb mRNA的选择性周转，这可能与这些逆转过程相对应。TIS11b基因敲除后，类固醇急性调节（STAR）蛋白诱导减少一半，同时胆固醇代谢降低。因此，令人惊讶的是，TIS11b对3.5 kb mRNA的抑制与Star翻译的增强相关联，从而导致胆固醇代谢增加。（分子内分泌学23:497-509,2009）
Star is expressed in steroidogenic cells as 3.5- and 1.6-kb transcripts that differ only in their 3'-untranslated regions (3'-UTR). In mouse MA10 testis and Y-1 adrenal lines, Br-cAMP preferentially stimulates 3.5-kb mRNA. ACTH is similarly selective in primary bovine adrenocortical cells. The 3.5-kb form harbors AU-rich elements (AURE) in the extended 3'-UTR, which enhance turnover. After peak stimulation of 3.5-kb mRNA, degradation is seen. Star mRNA turnover is enhanced by the zinc finger protein ZFP36L1/TIS11b, which binds to UAUUUAUU repeats in the extended 3'-UTR. TIS11b is rapidly stimulated in each cell type in parallel with Star mRNA. Co-transfection of TIS11b selectively decreases cytomegalovirus-promoted Star mRNA and luciferase-Star 3'-UTR reporters harboring the extended 3'-UTR. Direct complex formation was demonstrated between TIS11b and the extended 3'-UTR of the 3.5-kb Star. AURE mutations revealed that TIS11b-mediated destabilization required the first two UAUUUAUU motifs. HuR, which also binds AURE, did not affect Star expression. Targeted small interfering RNA knockdown of TIS11b specifically enhanced stimulation of 3.5-kb Star mRNA in bovine adrenocortical cells, MA-10, and Y-1 cells but did not affect the reversals seen after peak stimulation. Direct transfection of Star mRNA demonstrated that Br-cAMP stimulated a selective turnover of 3.5-kb mRNA independent of AURE, which may correspond to these reversal processes. Steroidogenic acute regulatory (STAR) protein induction was halved by TIS11b knockdown, concomitant with decreased cholesterol metabolism. TIS11b suppression of 3.5-kb mRNA is therefore surprisingly coupled to enhanced Star translation leading to increased cholesterol metabolism. (Molecular Endocrinology 23: 497-509, 2009)