Gonadal Receptors/Mechanisms Of Action Of Hormones

性腺受体/激素作用机制

• 批准号: 6811587
• 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/6811587
• 关键词: Leydig cells; genetic transcription; germ cells; hormone receptor; hormone regulation /control mechanism; human tissue; laboratory rat; luteinizing hormone; peptide hormone; prolactin; protein structure function; receptor expression; testis

The LH receptor: The luteinizing hormone receptor (LRH) is a TATAless gene whose transcription is driven by Sp1/Sp3. Functional studies on the mechanism of orphan receptor-mediated silencing of transcription of the luteinizing hormone receptor have established a functional connection between the orphan receptor EAR3/COUP-TFI bound to a DNA direct repeat and the Sp1/Sp3 complex. EAR3 perturbs the communication between Sp1/Sp3 at the Sp1 site and the basal transcription complex through TFIIB, and reduces recruitment of RNA Pol II. This mechanism has been found to be operative in repressive/inductive states of the LHR during the ovarian cycle. Control of testicular function:The gonadotropin-regulated testicular RNA helicase (GRTH/Ddx25) cloned in this Branch is novel member of the DEAD-box family. This testis-specific enzyme is present in Leydig and germ cells (pachytene spermatocytes, round spermatids), and is the first member found to be regulated by hormones (gonadotropin/androgen). Recent studies have identified three translation initiation codons that are utilized for the generation of multiple species. The studies have demonstrated a cell-specific and androgen-dependent alternative usage of ATG codons in the rat testis. The autocrine actions of testosterone in Leydig cells and paracrine actions at tubule sites (round spermatids) cause increases of GRTH at the transcriptional level and promote the utilization of the 2nd ATG codon in both cell types at the translational level. The Prolactin receptor: Acting through its cognate receptor (hPRLR-long form), prolactin activates Jak2/Stat5 pathway, which is essential for prolactin-induced differentiation of mammary epithelium. It was generally accepted that prolactin-induced homodimerization is required for the activation of subsequent signalling pathways. However,current studies demonstrated that homodimerization of the long form of the receptor can be independent of prolactin. They also demonstrated heterodimerization between the long form of the hPRLR (activating) and either of the two short forms discovered in the branch (dominant repressor forms), indicating that homodimers and heterodimers are constitutively present. The hormonal stimulus could act on the preformed homodimer of the long form to induce the signaling by causing changes in conformation of the cytoplasmic domain. Heterodimerization with either short form could abrogate the hormone-induced structural changes that are required for activation of the dimeric long form of the receptor.

LH 受体：黄体生成素受体 (LRH) 是一种 TATAless 基因，其转录由 Sp1/Sp3 驱动。对孤儿受体介导的黄体生成素受体转录沉默机制的功能研究已经建立了与DNA同向重复序列结合的孤儿受体EAR3/COUP-TFI与Sp1/Sp3复合物之间的功能联系。 EAR3 通过 TFIIB 扰乱 Sp1 位点的 Sp1/Sp3 与基础转录复合物之间的通讯，并减少 RNA Pol II 的募集。已发现这种机制在卵巢周期期间 LHR 的抑制/诱导状态下起作用。 睾丸功能的控制：该分支中克隆的促性腺激素调节的睾丸RNA解旋酶（GRTH/Ddx25）是DEAD-box家族的新成员。这种睾丸特异性酶存在于间质细胞和生殖细胞（粗线期精母细胞、圆形精子细胞）中，并且是第一个被发现受激素（促性腺激素/雄激素）调节的成员。最近的研究已经确定了用于产生多个物种的三个翻译起始密码子。研究表明，ATG 密码子在大鼠睾丸中存在细胞特异性和雄激素依赖性替代使用。间质细胞中睾酮的自分泌作用和小管位点（圆形精子细胞）的旁分泌作用导致转录水平上 GRTH 的增加，并促进两种细胞类型中翻译水平上第二个 ATG 密码子的利用。 催乳素受体：催乳素通过其同源受体（hPRLR-长形式）发挥作用，激活 Jak2/Stat5 通路，这对于催乳素诱导的乳腺上皮分化至关重要。人们普遍认为，催乳素诱导的同二聚化是随后信号通路激活所必需的。然而，目前的研究表明，长形式受体的同二聚化可以独立于催乳素。他们还证明了 hPRLR 的长形式（激活）与分支中发现的两种短形式（显性抑制形式）之间的异二聚化，表明同二聚体和异二聚体是组成型存在的。激素刺激可以作用于预先形成的长形式同二聚体，通过引起细胞质结构域构象的变化来诱导信号传导。任一短形式的异二聚化都可以消除激素诱导的结构变化，而这些结构变化是激活二聚体长形式受体所需的。