Tripathy Sudeshna, Nagari Anusha, Chiu Shu-Ping, Nandu Tulip, Camacho Cristel V, Mahendroo Mala, Kraus W Lee
Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Laboratory of Cervical Remodeling and Preterm Birth, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Endocrinology. 2024 Sep 26;165(11). doi: 10.1210/endocr/bqae123.
Estradiol (E2) and relaxin (Rln) are steroid and polypeptide hormones, respectively, with important roles in the female reproductive tract, including myometrium. Some actions of Rln, which are mediated by its membrane receptor RXFP1, require or are augmented by E2 signaling through its cognate nuclear steroid receptor, estrogen receptor alpha (ERα). In contrast, other actions of Rln act in opposition to the effects of E2. Here we explored the molecular and genomic mechanisms that underlie the functional interplay between E2 and Rln in the myometrium. We used both ovariectomized female mice and immortalized human myometrial cells expressing wild-type or mutant ERα (hTERT-HM-ERα cells). Our results indicate that Rln modulates the genomic actions and biological effects of estrogen in the myometrium and myometrial cells by reducing phosphorylation of ERα on serine 118 (S118), as well as by reducing the E2-dependent binding of ERα across the genome. These effects were associated with changes in the hormone-regulated transcriptome, including a decrease in the E2-dependent expression of some genes and enhanced expression of others. The inhibitory effects of Rln cotreatment on the E2-dependent phosphorylation of ERα required the nuclear dual-specificity phosphatases DUSP1 and DUSP5. Moreover, the inhibitory effects of Rln were reflected in a concomitant inhibition of the E2-dependent contraction of myometrial cells. Collectively, our results identify a pathway that integrates Rln/RXFP1 and E2/ERα signaling, resulting in a convergence of membrane and nuclear signaling pathways to control genomic and biological outcomes.
雌二醇（E2）和松弛素（Rln）分别是类固醇激素和多肽激素，在女性生殖道（包括子宫肌层）中发挥重要作用。Rln的一些作用由其膜受体RXFP1介导，这些作用需要E2通过其同源核类固醇受体雌激素受体α（ERα）发出的信号传导来实现或增强。相反，Rln的其他作用与E2的作用相反。在这里，我们探索了子宫肌层中E2和Rln之间功能相互作用的分子和基因组机制。我们使用了卵巢切除的雌性小鼠和表达野生型或突变型ERα的永生化人子宫肌层细胞（hTERT-HM-ERα细胞）。我们的结果表明，Rln通过降低ERα丝氨酸118（S118）位点的磷酸化，以及减少ERα在全基因组上与E2的依赖性结合，来调节雌激素在子宫肌层和子宫肌层细胞中的基因组作用和生物学效应。这些效应与激素调节的转录组变化相关，包括一些基因的E2依赖性表达降低，而其他一些基因的表达增强。Rln联合处理对ERα的E2依赖性磷酸化的抑制作用需要核双特异性磷酸酶DUSP1和DUSP5。此外，Rln的抑制作用还表现为对子宫肌层细胞E2依赖性收缩的同时抑制。总的来说，我们的结果确定了一条整合Rln/RXFP1和E2/ERα信号传导的途径，导致膜信号和核信号途径汇聚，以控制基因组和生物学结果。
