Regulation of TGF-beta Receptor Signaling by HSP90

改善人类癌症的前景只能来自于对 导致人类癌症的分子机制。一个重要的联系可能是 在转化生长因子_1信号与癌症之间产生作用。此应用程序的长期目标是 目的：阐明转化生长因子_1调控和功能的分子机制，以及 了解转化生长因子反应改变如何导致 放松对人类癌症生长控制的管制。 转化生长因子β既可作为肿瘤抑制因子，又可作为肿瘤的重要促进剂 进展、侵袭和转移。在肿瘤发生的早期阶段，转化生长因子β的缺失 生长抑制反应在癌症中很常见。然而，癌症通常会分泌 过量的转化生长因子α，并通过增加侵袭和转移而对其作出反应。短期内 我们的研究策略是将重点放在以下分子机制上 热休克蛋白90(HSP90)对正常上皮和正常皮肤组织中转化生长因子β信号的调节 肿瘤细胞。我们的初步研究首次证明了热休克蛋白90 抑制剂(如聚酮格尔达那霉素及其衍生物)能有效地阻断转化生长因子 回应。这一提议的统一假设是，HSP90是一种必不可少的 分子伴侣在维持活跃的转化生长因子信号转导中的作用为了检验这一假设，我们 将进行生化和细胞生物学研究，以确定HSP90如何调节 转化生长因子介导的下游信号通路激活及其生理性 正常细胞和肿瘤细胞的反应。考虑到部分完成 最初提出的研究和两年的分配时间框架，两个重要的 提出了具体的目标，以适应范围的缩小，但没有 牺牲科学意义：1.充分描述分子间的相互作用 热休克蛋白90与转化生长因子受体之间的关系；2.探讨热休克蛋白90的作用 阻断转化生长因子诱导的EMT、侵袭和肿瘤转移的抑制剂。这个 拟议的研究不仅应该深入了解HSP90抑制剂对 TGF_Growth-调节反应，但也提供了关于使用的宝贵信息 用于治疗人类癌症的HSP90抑制剂。

Improving the outlook for human cancer can only come from a better understanding of the molecular mechanisms that cause human cancer. An important connection can be made between TGF_ signaling and cancer. The long-term objective of this application is to elucidate the molecular mechanisms underlying TGF_ regulation and functions, and understand the molecular basis of how alterations in TGF_ responses lead to deregulation of growth control in human cancer. TGF_ can act as both a tumor suppressor and as a significant promoter of tumor progression, invasion and metastasis. At early stages of tumorigenesis, loss of TGF_ growth inhibitory responses is frequent in cancers. However, carcinomas often secrete excess TGF_ and respond to it by enhanced invasion and metastasis. The short-term strategy of our research is to focus on the molecular mechanisms underlying the regulation of TGF_ signaling by heat shock protein 90 (HSP90) in normal epithelial and tumor cells. Our preliminary studies have demonstrated, for the first time, HSP90 inhibitors (e.g. the polyketide geldanamycin and derivatives), potently block TGF_ responses. The unifying hypothesis of this proposal is that HSP90 is an essential molecular chaperone in maintaining active TGF_ signaling. To test this hypothesis, we will undertake biochemical and cell biological studies to determine how HSP90 regulates TGF_-mediated activation of downstream signaling pathways and physiological responses in normal and tumor cells. Considering the partial completion of the originally proposed studies and the two-year allotted time frame, two important specific aims are proposed to accommodate the scope reduction yet without sacrificing scientific significance: 1. To fully characterize the molecular interplay between HSP90 and TGF_ receptors; 2. To investigate the effects of HSP90 inhibitors in blocking TGF_-induced EMT, invasiveness and tumor metastasis. The proposed studies should not only gain insights into the effects of HSP90 inhibitors on TGF_ growth-regulatory responses, but also provide invaluable information on the use of HSP90 inhibitors to treat human cancers.