Yang Zuocheng, Wolf Irene M, Chen Hanying, Periyasamy Sumudra, Chen Zhuang, Yong Weidong, Shi Shu, Zhao Weihong, Xu Jianming, Srivastava Arun, Sánchez Edwin R, Shou Weinian
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Mol Endocrinol. 2006 Nov;20(11):2682-94. doi: 10.1210/me.2006-0024. Epub 2006 Jul 27.
FK506-binding protein 52 (FKBP52) is a tetratricopeptide repeat protein that associates with steroid receptors in complexes containing heat shock protein 90. To investigate the role of FKBP52 in steroid-regulated physiology, we generated FKBP52-deficient mice. FKBP52 (-/-) females are sterile due to a complete failure of implantation, a process that requires estrogen (ER) and progesterone receptors (PR). Because the uterus expresses two forms of PR, PR-A and PR-B, we investigated all three receptors as potential targets of FKBP52 action. FKBP52 (-/-) uteri showed a normal growth response to estradiol, and unaltered expression of genes controlled by ER and PR-B. In contrast, FKBP52 (-/-) uteri were neither able to express two PR-A-regulated genes, nor undergo decidualization in response to progesterone, suggesting that FKBP52 specifically regulates PR-A at this organ. Analysis of uterine PR heterocomplexes showed preferential association of FKBP52 with PR-A compared with PR-B. Loss of FKBP52 neither disrupted the PR-A/heat shock protein 90 interaction, nor impaired uterine PR-A hormone-binding function, demonstrating the essential role of FKBP52 in PR-A action to be downstream of the hormone-binding event. Transcription studies in +/+ and -/- mouse embryonic fibroblast cells showed a near-complete loss of PR-A activity at mouse mammary tumor virus and synthetic progesterone response element promoters, although partial reductions of ER and PR-B were also observed. Partial disruptions of ovulation and mammary development were also found in FKBP52 (-/-) females. Taken as a whole, our results show FKBP52 to be an essential regulator of PR-A action in the uterus, while being a nonessential but contributory regulator of steroid receptors in the mammary and ovary. These data may now provide the basis for selective targeting of steroid-regulated physiology through tetratricopeptide repeat proteins.
FK506结合蛋白52（FKBP52）是一种四肽重复蛋白，在含有热休克蛋白90的复合物中与类固醇受体结合。为了研究FKBP52在类固醇调节生理过程中的作用，我们培育了FKBP52基因缺失的小鼠。FKBP52（-/-）雌性小鼠由于完全无法着床而不育，着床过程需要雌激素（ER）和孕激素受体（PR）。由于子宫表达两种形式的PR，即PR-A和PR-B，我们研究了这三种受体作为FKBP52作用潜在靶点的情况。FKBP52（-/-）子宫对雌二醇显示出正常的生长反应，且由ER和PR-B控制的基因表达未改变。相比之下，FKBP52（-/-）子宫既无法表达两个受PR-A调控的基因，也不能对孕激素产生蜕膜反应，这表明FKBP52在该器官中特异性调节PR-A。对子宫PR异源复合物的分析表明，与PR-B相比，FKBP52与PR-A的结合更具选择性。FKBP52的缺失既未破坏PR-A/热休克蛋白90的相互作用，也未损害子宫PR-A的激素结合功能，这表明FKBP52在PR-A作用中的关键作用是在激素结合事件的下游。在野生型和基因缺失型小鼠胚胎成纤维细胞中的转录研究表明，在小鼠乳腺肿瘤病毒和合成孕激素反应元件启动子处，PR-A活性几乎完全丧失，尽管也观察到ER和PR-B有部分降低。在FKBP52（-/-）雌性小鼠中还发现排卵和乳腺发育存在部分障碍。总体而言，我们的结果表明FKBP52是子宫中PR-A作用的关键调节因子，而在乳腺和卵巢中是类固醇受体的非关键但有促进作用的调节因子。这些数据现在可能为通过四肽重复蛋白选择性靶向类固醇调节的生理过程提供基础。
