Conneely O M, Mulac-Jericevic B, Lydon J P, De Mayo F J
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Mol Cell Endocrinol. 2001 Jun 20;179(1-2):97-103. doi: 10.1016/s0303-7207(01)00465-8.
Progesterone plays a central coordinate role in diverse reproductive events associated with establishment and maintenance of pregnancy. In humans and other vertebrates, the biological activities of progesterone are mediated by two proteins, A (PR-A) and B (PR-B) that arise from the same gene and function as progesterone activated transcription factors that exhibit different transcription regulatory activities in vitro. Mice lacking both PR isoforms (PRKO mice) exhibit pleiotropic reproductive abnormalities. To address the physiological role of the individual isoforms, we have selectively ablated PR-A expression in mice (PRAKO). We have demonstrated that PR-B mediates a subset of the reproductive functions of P. Ablation of PR-A does not affect responses of the mammary gland or thymus to P but results in severe abnormalities in ovarian and uterine function. Analysis of urine function of PRAKP mice reveals an unexpected P-dependent proliferative activity of PR-B in the epithelium and provides evidence that the tissue-specific reproductive effects of this isoform are due to specificity of target gene transactivation rather than differences in tissue-specific expression relative to PR-A. Taken together, our data indicate that PR-A and PR-B act in vivo as two functionally distinct transcription factors.
孕酮在与妊娠的建立和维持相关的各种生殖事件中发挥着核心协调作用。在人类和其他脊椎动物中，孕酮的生物学活性由两种蛋白质介导，即A（PR-A）和B（PR-B），它们源自同一基因，作为孕酮激活的转录因子发挥作用，在体外表现出不同的转录调节活性。缺乏两种PR异构体的小鼠（PRKO小鼠）表现出多效性生殖异常。为了研究单个异构体的生理作用，我们在小鼠中选择性地敲除了PR-A的表达（PRAKO）。我们已经证明，PR-B介导了孕酮的一部分生殖功能。敲除PR-A并不影响乳腺或胸腺对孕酮的反应，但会导致卵巢和子宫功能出现严重异常。对PRAKO小鼠尿液功能的分析揭示了PR-B在上皮细胞中意外的孕酮依赖性增殖活性，并提供了证据表明该异构体的组织特异性生殖效应是由于靶基因反式激活的特异性，而不是相对于PR-A在组织特异性表达上的差异。综上所述，我们的数据表明PR-A和PR-B在体内作为两种功能不同的转录因子发挥作用。
