Regulation of TGF-beta Receptor Signaling by HSP90

改善人类癌症的前景只能来自更好地了解 导致人类癌症的分子机制一个重要的联系可能是 在TGF信号和癌症之间的联系。该应用程序的长期目标是 阐明TGF β 1调节和功能的分子机制， 了解TGF_反应的改变如何导致 人类癌症生长控制的失调。 TGF-β_2既有抑癌作用，又有促癌作用 进展、侵袭和转移。在肿瘤发生的早期阶段，TGF-β_1的丢失可能与肿瘤的发生有关。 生长抑制反应在癌症中是常见的。然而，癌细胞经常分泌 TGF-β 1表达增加，并通过增强侵袭和转移而对其作出反应。短期 我们的研究策略是关注潜在的分子机制， 热休克蛋白90（HSP 90）对正常上皮细胞TGF-β_2信号的调节 肿瘤细胞我们的初步研究首次证明，HSP 90 抑制剂（例如聚酮格尔德霉素和衍生物），有效地阻断TGF-β 1。 应答这个建议的统一假设是，HSP 90是一个必不可少的， 分子伴侣在维持TGF β_1信号转导中的作用。为了验证这个假设，我们 将进行生物化学和细胞生物学研究，以确定HSP 90如何调节 TGF-β 1介导的下游信号通路的激活和生理 正常细胞和肿瘤细胞的反应。考虑到部分完成的 在最初提议的研究和分配的两年时间框架内， 提出了具体的目标，以适应范围缩小，但没有 牺牲科学意义：1.为了充分描述分子间的相互作用 HSP 90与TGF-β 1受体的关系; 2.探讨热休克蛋白90（HSP 90）对人肝癌细胞增殖的影响 抑制剂阻断TGF-β诱导的EMT、侵袭和肿瘤转移。的 拟议的研究不仅应该深入了解HSP 90抑制剂对 TGF_生长调节反应，而且还提供了关于使用 HSP 90抑制剂来治疗人类癌症

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.