Yuan Bin, Yang Jing, Dubeau Louis, Hu Yanfen, Li Rong
Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, United States.
Department of Pathology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States.
Front Cell Dev Biol. 2021 Apr 9;9:649087. doi: 10.3389/fcell.2021.649087. eCollection 2021.
The two homologous estrogen receptors ERα and ERβ exert distinct effects on their cognate tissues. Previous work from our laboratory identified an ERβ-specific phosphotyrosine residue that regulates ERβ transcriptional activity and antitumor function in breast cancer cells. To determine the physiological role of the ERβ phosphotyrosine residue in normal tissue development and function, we investigated a mutant mouse model (Y55F) whereby this particular tyrosine residue in endogenous mouse ERβ is mutated to phenylalanine. While grossly indistinguishable from their wild-type littermates, mutant female mice displayed reduced fertility, decreased ovarian follicular cell proliferation, and lower progesterone levels. Moreover, mutant ERβ from female mice during superovulation is defective in activating promoters of its target genes in ovarian tissues. Thus, our findings provide compelling genetic and molecular evidence for a role of isotype-specific ERβ phosphorylation in mouse ovarian development and function.
两种同源雌激素受体ERα和ERβ对其相应组织发挥不同作用。我们实验室之前的研究确定了一个ERβ特异性磷酸酪氨酸残基，它可调节乳腺癌细胞中ERβ的转录活性和抗肿瘤功能。为了确定ERβ磷酸酪氨酸残基在正常组织发育和功能中的生理作用，我们研究了一种突变小鼠模型（Y55F），其中内源性小鼠ERβ中的这个特定酪氨酸残基被突变为苯丙氨酸。虽然突变雌性小鼠与它们的野生型同窝小鼠在外观上没有明显差异，但它们的生育能力下降，卵巢卵泡细胞增殖减少，孕酮水平降低。此外，超排卵期间雌性小鼠的突变ERβ在激活卵巢组织中其靶基因的启动子方面存在缺陷。因此，我们的研究结果为同种型特异性ERβ磷酸化在小鼠卵巢发育和功能中的作用提供了令人信服的遗传和分子证据。
