Shao Ruijin, Weijdegård Birgitta, Ljungström Karin, Friberg Anders, Zhu Changlian, Wang Xiaoyang, Zhu Yihong, Fernandez-Rodriguez Julia, Egecioglu Emil, Rung Emilia, Billig Håkan
Section of Endocrinology, Dept. of Physiology and Pharmacology, Sahlgrenska Academy, Göteborg University, SE-40530, Gothenburg, Sweden.
Am J Physiol Endocrinol Metab. 2006 Jul;291(1):E59-72. doi: 10.1152/ajpendo.00582.2005. Epub 2006 Jan 31.
Progesterone and its interaction with nuclear progesterone receptors (PR) PR-A and PR-B play a critical role in the regulation of female reproductive function in all mammals. However, our knowledge of the regulation and possible cellular function of PR protein isoforms in the fallopian tube and uterus in vivo is still very limited. In the present study, we revealed that equine chorionic gonadotropin (eCG) treatment resulted in a time-dependent increase in expression of both isoforms, reaching a maximal level at 48 h in the fallopian tube. Regulation of PR-A protein expression paralleled that of PR-B protein expression. However, in the uterus PR-B protein levels increased and peaked earlier than PR-A protein levels after eCG treatment. With prolonged exposure to eCG, PR-B protein levels decreased, whereas PR-A protein levels continued to increase. Furthermore, subsequent treatment with human (h)CG decreased the levels of PR protein isoforms in both tissues in parallel with increased endogenous serum progesterone levels. To further elucidate whether progesterone regulates PR protein isoforms, we demonstrated that a time-dependent treatment with progesterone (P(4)) decreased the expression of PR protein isoforms in both tissues, whereas decreases in p27, cyclin D(2), and proliferating cell nuclear antigen protein levels were observed only in the uterus. To define the potential PR-mediated effects on apoptosis, we demonstrated that the PR antagonist treatment increased the levels of PR protein isoforms, induced mitochondrial-associated apoptosis, and decreased in epidermal growth factor (EGF) and EGF receptor protein expression in both tissues. Interestingly, immunohistochemistry indicated that the induction of apoptosis by PR antagonists was predominant in the epithelium, whereas increase in PR protein expression was observed in stromal cells of both tissues. Taken together, these observations suggest that 1) the tissue-specific and hormonal regulation of PR isoform expression in mouse fallopian tube and uterus, where they are potentially involved in regulation of mitochondrial-mediated apoptosis depending on the cellular compartment; and 2) a possible interaction between functional PR protein and growth factor signaling may have a coordinated role for regulating apoptotic process in both tissues in vivo.
孕酮及其与核孕酮受体（PR）的PR-A和PR-B亚型的相互作用在所有哺乳动物雌性生殖功能的调节中起着关键作用。然而，我们对体内输卵管和子宫中PR蛋白亚型的调节及其可能的细胞功能的了解仍然非常有限。在本研究中，我们发现马绒毛膜促性腺激素（eCG）处理导致两种亚型的表达随时间增加，在输卵管中48小时达到最高水平。PR-A蛋白表达的调节与PR-B蛋白表达的调节平行。然而，在子宫中，eCG处理后PR-B蛋白水平升高且峰值早于PR-A蛋白水平。随着eCG暴露时间延长，PR-B蛋白水平下降，而PR-A蛋白水平持续升高。此外，随后用人绒毛膜促性腺激素（hCG）处理会使两个组织中PR蛋白亚型水平降低，同时内源性血清孕酮水平升高。为了进一步阐明孕酮是否调节PR蛋白亚型，我们证明用孕酮（P4）进行时间依赖性处理会降低两个组织中PR蛋白亚型的表达，而仅在子宫中观察到p27、细胞周期蛋白D2和增殖细胞核抗原蛋白水平降低。为了确定PR介导的对细胞凋亡的潜在影响，我们证明PR拮抗剂处理会增加PR蛋白亚型水平，诱导线粒体相关凋亡，并降低两个组织中表皮生长因子（EGF）和EGF受体蛋白表达。有趣的是，免疫组织化学表明PR拮抗剂诱导的细胞凋亡在上皮细胞中占主导，而在两个组织的基质细胞中观察到PR蛋白表达增加。综上所述，这些观察结果表明：1）小鼠输卵管和子宫中PR亚型表达的组织特异性和激素调节，在那里它们可能根据细胞区室参与线粒体介导的细胞凋亡调节；2）功能性PR蛋白与生长因子信号之间的可能相互作用可能在体内调节两个组织的细胞凋亡过程中起协同作用。
