MicroRNA-122: a new player in the negative regulation of LH receptor expression by the LH receptor mRNA binding protein (LRBP).
MicroRNA-122: a new player in the negative regulation of LH receptor expression by the LH receptor mRNA binding protein (LRBP).
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DOI：
10.1210/en.2013-1897
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发表时间：
2013-12
期刊：
影响因子：
4.8
通讯作者：
S. Azhar
中科院分区：
文献类型：
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作者：
S. Azhar
黄体生成素受体(LHR)在卵巢类固醇生成细胞(卵泡膜细胞、颗粒细胞和黄体细胞)和睾丸(间质细胞)的促黄体生成激素作用中起重要作用。它属于G蛋白偶联受体超家族，具有7个跨膜区(1)，是研究最多的多肽激素受体之一。在20世纪70年代早期到中期(2-10年)对其激素结合特性进行了广泛的鉴定之后，在接下来的40年左右的时间里，对LHR的各种功能的认识取得了巨大的进展，包括细胞信号的调节(11-14)，类固醇生成急性调节蛋白(STAR)的表达，将胆固醇运输到线粒体膜内侧链裂解的蛋白(P450scc，CyP11A)(14-17)，通过低密度脂蛋白受体介导的内源性和选择性地将外源性胆固醇输送到类固醇生成细胞(分别为B型，18-21)，以及与从细胞内储存物中动员胆固醇(22，23)和细胞胆固醇运输(17，24)相关的事件。然而，对LHR表达的分子和细胞调控知之甚少(11，12)。直到最近，根据现有的数据，人们普遍认为LHR的表达主要是在基因转录水平上调节的(1，11)。然而，近年来，密歇根大学曾傑瑞·梅农博士的实验室进行的开创性研究导致人们意识到，LHR也受到转录后水平的影响(25，26)。事实上，现在的压倒性证据表明，这些机制是促黄体生成素诱导的LHR下调的主要因素。梅农和他的同事们报道的初步研究表明，甲伐他酸激酶(MVK)的表达在促进抑制LHR表达的条件下上调(27-29)。甲伐他酸激酶(MVK)是参与胆固醇生物合成的关键酶，它催化甲氧丙酮酸转化为5-磷酸蛋氨酸。后续研究表明，MVK可以直接与LHR mRNA编码区结合，抑制其翻译能力(27-31)；由于这一特殊功能，MVK被Menon实验室重新命名为“LHR mRNA结合蛋白(LRBP)”。大鼠和人的颗粒细胞也表达高水平的LRBP，功能研究表明它干扰LHR表达的方式与黄体卵巢相似(32-34)。MVK(LRBP)活性的存在已在大鼠睾丸间质细胞中被证实，但到目前为止还没有对促黄体生成素反应的间质细胞进行功能研究。最近的研究表明，除促性腺激素外，MVK/LRBP还受胆固醇反应转录因子-1a(SREBP-1a)和SREBP-2(36)的转录调控。这些不同的发现可以解释为卵巢类固醇激素的生物合成是通过作用于LHR mRNA表达水平的共同调节机制来整合的，该生物合成受LHR调节，并依赖于胆固醇代谢来获得胆固醇底物。
The LH receptor (LHR) plays an essential role in mediating LH actions in the steroidogenic cells of the ovary (theca, granulosa, and luteal cells) and testis (Leydig cells). It belongs to the G protein-coupled superfamily of receptors with seven transmembrane domains (1) and it is one of the most studied peptide hormone receptors. After extensive characterization of its hormone binding properties in the early to mid 1970s (2–10), in the ensuing 40 years or so, tremendous progress has been made in understanding various functions of the LHR, including the regulation of cellular signaling (11–14), expression of steroidogenic acute regulatory protein (StAR), the protein that transports cholesterol to the inner mitochondrial membrane for side-chain cleavage (P450scc, CYP11A) (14–17), endocytic and selective delivery of exogenous cholesterol to the steroidogenic cells mediated by low-density lipoprotein receptor, and scavenger receptor class B, type, respectively (18–21), and the events connected with the mobilization of cholesterol from the intracellular stores (22, 23) and the cellular cholesterol trafficking (17, 24). However, relatively less is known about the molecular and cellular regulation of LHR expression (11, 12). Until recently, based on the available data, it was generally believed that LHR expression is primarily regulated at the level of gene transcription (1, 11). In recent years, however, the seminal studies carried out by Dr Jerry Menon's laboratory at the University of Michigan have led to the realization that LHR is also subject to posttranscription (25, 26). In fact, the overwhelming evidence now suggests that these mechanisms are major contributors to the LH-induced down-regulation of LHR. Initial studies reported by Menon and colleagues demonstrated that the expression of mevalonate kinase (MVK), a key enzyme involved in cholesterol biosynthesis, that catalyzes the conversion of mevalonic acid to 5-phosphomevalonic acid, is up-regulated under the conditions that promote the repression of the LHR expression (27–29). The follow-up studies demonstrated that MVK can directly bind to the coding region of LHR mRNA and inhibits its translational capacity (27–31); because of this specialized function, MVK was renamed by the Menon laboratory as “LHR mRNA binding protein (LRBP).” Both rat and human granulosa cells also express high levels of LRBP and the functional studies demonstrated that it interferes with the LHR expression in a manner similar to that seen in the luteinized ovary (32–34). The presence to MVK (LRBP) activity has been demonstrated in the interstitial cells of rat testis (35) but so far no functional studies have been carried out in LH responsive Leydig cells. Recent evidence suggests that in addition to gonadotropin, MVK/LRBP, a member of the oxysterol responsive gene family, is also regulated transcriptionally by the cholesterol responsive transcription factors, sterol regulatory element-binding protein-1a (SREBP-1a) and SREBP-2 (36). These various findings can be interpreted to suggest that ovarian steroid hormone biosynthesis, which is under LH regulation via LHR and is dependent on the cholesterol metabolism for the availability of cholesterol substrate, are integrated through a common regulatory mechanism acting at the level of LHR mRNA expression.