GONADAL RECEPTORS/MECHANISMS OF ACTION OF PEPTIDE HORMONES IN STEROIDOGENIC CELL

性腺受体/肽激素在类固醇细胞中的作用机制

• 批准号: 6432496
• 负责人: MARIA DUFAU
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6432496
• 关键词: corticotropin releasing factor; cysteine; genetic mapping; genetic promoter element; genetic transcription; hormone receptor; hormone regulation /control mechanism; hydroxysteroid dehydrogenases; introns; isozymes; luteinizing hormone; molecular site; peptide hormone; prolactin; protein folding; protein isoforms; protein sequence; protein structure function; receptor binding; receptor expression; steroid hormone metabolism; tissue /cell culture

1) The LH receptor: The 176 bp human/rat promoter domain of the LH receptor (LHR) TATAless gene contains two Sp1/Sp3 binding domains of central importance for transcription. An imperfect estrogen receptor half-site response element direct-repeat (D0), located within the promoter 5'to the Sp1 sites, was identified in the human gene as an inhibitory site for the Sp1/Sp3 driven transcription. Dimeric nuclear receptors EAR2, EAR3/COUP-TF1 and TR4 (nuclear extracts, rat, human testis or in vitro translated) bound the direct-repeat of the LHR promoter. Functional analyses in CV1 cells (devoid of orphans) demonstrated that EAR2 and EAR3 repress and TR4 stimulates transcriptional activity through binding the same cis-element. The stimulation was reversed by coexpression of EAR2 or EAR3 indicating competition for this site. Such recognition of a common site by proteins with antagonist functions implies that the net/regulation/ and or expression of the hLHR gene may result from the relative availability of repressor and activator in the organ and physiological state. This may also contribute to the differential expression of the LHR gene in gonadal and non-gonadal tissues. 2) Gonadotropin regulation: A novel gonadotropin-regulated testicular RNA helicase (GRTH) cloned from rat Leydig cell, mouse and human testis cDNA libraries is a novel member of the DEAD-box protein family. GTRH displayed ATPase and RNA helicase activities and stimulated translation of RNA templates. This helicase is highly expressed in rat, mouse and human testes and weakly in the pituitary and hypothalamus. GRTH expressed in Leydig and meiotic cells is developmentally regulated. GRTH is transcriptionally up-regulated by hCG via cAMP-induced androgen formation in the Leydig cell. This novel helicase could be relevant to the control of steroidogenesis and the paracrine regulation of androgen- dependent spermatogenesis in the testis. 3) Leptin in Leydig cell function: Rat Leydig cells express both isoforms of leptin. Leptin cause an acute inhibition of hCG stimulated testosterone production. This was accompanied by a significant reduction of androstenedione and a rise of proximal steroid precursors indicating a leptin-induced lesion of 17,20 lyase activity. The results have implications in some clinical aspects of male reproduction, such as the reduced testicular function in obese males.

1）LH受体：LH受体（LHR）Tataless基因的176 bp人/大鼠启动子结构域包含两个SP1/SP3结合结构域，对转录具有核心重要性。在启动子5'TO中，SP1位点内的不完善的雌激素受体的半位点反应元件直接重复（D0）被鉴定为人类基因中的SP1/SP3驱动转录。 二聚体核受体EAR2，EAR3/COUP-TF1和TR4（核提取物，大鼠，人睾丸或体外翻译）结合了LHR启动子的直接重复。 CV1细胞（缺乏孤儿）的功能分析表明，EAR2和EAR3抑制和TR4通过结合相同的顺式元素刺激转录活性。通过EAR2或EAR3的共表达表明该站点竞争的刺激反转。 具有拮抗剂功能的蛋白质对共同位点的这种识别意味着HLHR基因的净/调节/和/或表达可能是由于器官和生理状态中阻遏物和激活剂的相对可用性而引起的。这也可能有助于在性腺和非基达组织中LHR基因的差异表达。 2）促性腺激素调节：一种新型的促性腺激素调节的睾丸RNA解旋酶（GRTH），它是从大鼠leydig细胞，小鼠和人睾丸cDNA库中克隆的，是Dead-box蛋白家族的新成员。 GTRH表现出ATPase和RNA解旋酶活性以及RNA模板的刺激翻译。 该解旋酶在大鼠，小鼠和人睾丸中高度表达，在垂体和下丘脑中弱表达。在Leydig和减数分裂细胞中表达的GRTH受发展调节。 HCG通过cAMP诱导的Leydig细胞中的雄激素形成在转录上被转录上调。这种新型解旋酶可能与睾丸中雄激素依赖性精子发生的类固醇生成和旁分泌调节有关。 3）Leydig细胞功能中的瘦素：大鼠Leydig细胞表达瘦素的两种同工型。瘦素引起急性抑制HCG刺激的睾丸激素产生。这伴随着雄激素的显着降低，近端类固醇前体的升高表明瘦素诱导的17,20裂解酶活性的病变。结果在男性繁殖的某些临床方面具有影响，例如肥胖雄性的睾丸功能降低。