TPR Proteins in Steroid Receptor Signaling & Physiology

描述（由申请人提供）：类固醇受体（SRs）是激素激活的转录因子，控制组织特异性基因表达和治疗上重要的生理机能。在无活性状态下，已知这些受体与伴侣蛋白Hsp90形成复合物，而Hsp90又可以与四种四肽重复（TPR）蛋白之一结合：FKBP52、FKBP51、Cyp40和PP5。这一事实意味着SRs存在于由TPR蛋白含量定义的不同异质复合物中。如果这些不同的复合体存在，它们一定有不同的功能。然而我们对这些微分函数几乎一无所知。我们现在有新的证据表明，TPR蛋白可以调节细胞内SR信号的不同阶段，以及组织对类固醇的特异性反应。这些结论是根据我们实验室的主要观察得出的。我们已经发现了激素激活糖皮质激素受体（GR）的一个新的第一步，涉及GR复合物中FKBP51与FKBP52的协调交换。这种TPR交换是告诉GR复合体招募运输蛋白动力蛋白并移动到细胞核的信号。我们还确定FKBP52、PP5和FKBP51对GR的激素结合功能具有分层影响，Cyp40可以调节GR蛋白水平并使其成为核。最后但并非最不重要的是，我们已经产生了FKBP52基因敲除小鼠，表现出雌性不育。进一步的表征表明，不孕不育是由于子宫内PR-A孕激素受体异构体不活跃，导致植入失败。有趣的是，PR-B亚型和子宫组织中的雌激素受体都不受FKBP52缺失的影响。因此，现在很清楚，不同的tpr会对生理产生受体和组织特异性的影响。考虑到这一点，本提案的目标是在无细胞和组织培养条件下进一步确定TPR蛋白在GR和PR功能中的作用，然后使用FKBP52和FKBP51敲除动物测试选择生理反应的机制。更好地了解TPR蛋白对GR和PR的差异作用，现在可以为针对生育和其他生理的新治疗策略奠定基础。

DESCRIPTION (provided by applicant): Steroid receptors (SRs) are hormone-activated transcription factors controlling tissues-specific gene expression and therapeutically important physiologies. In their inactive states, these receptors are known to form complexes with the chaperone Hsp90 which in turn can be bound by one of four tetratricopeptide repeat (TPR) proteins: FKBP52, FKBP51, Cyp40 and PP5. This fact means that SRs exists in distinct heteromeric complexes defined by TPR protein content. If these distinct complexes exist, they must have distinct functions. Yet we know almost nothing of these differential functions. We now have new evidence to suggest that TPR proteins serve to regulate distinct stages of SR signaling within a cell, as well as tissue specific responses to steroids. We base these conclusions on key observations from our laboratories. We have uncovered a new first step in hormonal activation of the glucocorticoid receptor (GR) that involves a coordinated exchange of FKBP51 for FKBP52 within GR complexes. This TPR exchange is the signal that tells GR complexes to recruit the transport protein dynein and move to the nucleus. We have also determined that FKBP52, PP5 and FKBP51 have hierarchical effects on the hormone-binding function of the GR, and that Cyp40 can regulate both GR protein levels and cause it to become nuclear. Last but not least, we have generated FKBP52 knockout mice that manifest female sterility. Further characterization has revealed the infertility to result from inactivity in the uterus by the PR-A progesterone receptor isoform, leading to a failure of implantation. Interestingly, both the PR-B isoform and the estrogen receptor in uterus tissue were unaffected by loss of FKBP52. Thus, it is now clear that distinct TPRs will have both receptor- and tissue-specific impacts on physiology. With this in mind, the goals of this proposal are to further define the roles of TPR proteins in GR and PR functions under cell-free and tissue culture conditions, followed by testing of mechanisms in select physiological responses using FKBP52 and FKBP51 knockout animals. A better understanding of differential TPR protein effects on both GR and PR could now form the basis for new therapeutic strategies targeting fertility and other physiologies.