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Crosstalk between post-translational regulations of the FNIP co-chaperones and their impact on Hsp90 chaperone function and drug binding

FNIP 共伴侣翻译后调控之间的串扰及其对 Hsp90 伴侣功能和药物结合的影响

基本信息

批准号：
9900840
负责人：
Mehdi Mollapour
金额：
$ 31.19万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2022-03-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY The molecular chaperone Heat Shock Protein-90 (Hsp90) is considered to be a critical facilitator of oncogene addiction and cancer cell survival. Hsp90 function is coupled to its ATPase activity, which is regulated by co-chaperones and posttranslational modifica- tions (PTMs). Hsp90 inhibitors are currently being evaluated in various stages of clinical trials in cancer patients. However, the optimal use of Hsp90-targeted therapy remains unknown. This is partly due to the limited knowledge of Hsp90 regulation in cancer cells. Folliculin-interacting proteins (FNIP-1 and 2), also known as FNIPs, are the newly dis- covered co-chaperones that decelerate Hsp90 activity. FNIPs compete with the activat- ing co-chaperone Aha1 for binding to Hsp90 and FNIPs expression correlates with the cellular response to Hsp90 inhibitors. It was also shown that PTMs (phosphorylation, O- GlcNAcylation, ubiquitination) of FNIPs and Aha1 affect their binding to Hap90, however, the detailed crosstalk between these PTMs and their impact on drug sensitivity remains unknown. Without this knowledge, optimal Hsp90-targeted therapeutics remains limited. The long-term goal of this proposal is to enhance the activity of the Hsp90 inhibitors in cancer cells by targeting the regulators of Hsp90. The overall objective is to determine the crosstalk between PTMs of co-chaperones in regulating Hsp90 function and how they contribute towards drug sensitivity. The central hypothesis is that PTMs of the FNIPs and Aha1 co-chaperones reciprocally impact their binding to Hsp90 and influence the potency of its drugs in cancer cells. The rationale of this proposal is that, by under- standing the impact of PTMs on co-chaperones association with Hsp90 and consequent- ly drug binding, it could be possible to target those enzymes responsible for the PTMs, therefore increasing the potency of Hsp90 inhibitors in cancer cells. Biochemical, bio- physical and cell-based assays as well as cancer cell lines will be used to test the hy- pothesis in the following specific aims; Aim 1: Determine the impact of crosstalk between phosphorylation and O-GlcNAcylation on co-chaperone activity of the FNIPs. Aim 2: De- termine the reciprocal role of FNIP1 and Aha1 co-chaperones on Hsp90 regulation. Aim 3: Determine the mechanism of FNIP co-chaperones on increasing the activity of Hsp90 inhibitors. In determining the interplay between FNIPs and Aha1 co-chaperones and how PTMs of these two proteins impact their binding to Hsp90, it is expected to unravel new targets to increase the potency of Hsp90 inhibitors in cancer cells.

项目摘要分子伴侣热休克蛋白90（Hsp 90）被认为是一个关键的促进癌基因成瘾和癌细胞存活。Hsp 90功能与其 ATP酶活性，这是由共伴侣和翻译后修饰调节，（PTM）。Hsp 90抑制剂目前正在临床治疗的各个阶段进行评估。在癌症患者中进行的试验。然而，Hsp 90靶向治疗的最佳使用仍然是未知这部分是由于对癌细胞中Hsp 90调节的了解有限。卵泡素相互作用蛋白（FNIP-1和2），也被称为FNIP，是新近发现的一种新的蛋白质。覆盖了减缓Hsp 90活性的辅助分子伴侣。FNIP与Activat竞争- 共同伴侣蛋白Aha 1与Hsp 90和FNIPs表达的结合与Hsp 90和FNIPs的表达相关。细胞对Hsp 90抑制剂的反应。研究还表明，PTMs（磷酸化，O- FNIP和Aha 1的GlcNAc酰化，泛素化）影响它们与Hap 90的结合，然而，这些PTM之间的详细串扰及其对药物敏感性的影响仍然存在未知没有这些知识，最佳的Hsp 90靶向治疗仍然有限。该提案的长期目标是增强Hsp 90抑制剂在体内的活性。通过靶向Hsp 90的调节剂来治疗癌细胞。总体目标是确定辅助分子伴侣蛋白PTM在调节Hsp 90功能中的相互作用及其机制它们有助于药物敏感性。中心假设是， FNIPs和Aha 1共分子伴侣共同影响它们与Hsp 90的结合，其药物在癌细胞中的效力。这一建议的基本原理是，通过在- 坚持PTM对与Hsp 90相关的共分子伴侣的影响，以及随之而来的- 在药物结合方面，有可能靶向那些负责PTM的酶，因此增加了Hsp 90抑制剂在癌细胞中的效力。生物化学，生物- 将使用物理和基于细胞的测定以及癌细胞系来测试hy，目标1：确定串扰在以下特定目标中的影响：磷酸化和O-GlcNAc化对FNIP的共伴侣活性的影响。目标2：确定FNIP 1和Aha 1共同伴侣在Hsp 90调控中的相互作用。目的 3：确定FNIP共分子伴侣增加Hsp 90活性的机制抑制剂的在确定FNIPs和Aha 1共同伴侣之间的相互作用以及如何这两种蛋白质的PTM影响它们与Hsp 90的结合，预计将揭示新的靶向增加Hsp 90抑制剂在癌细胞中的效力。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dubé: chaperones in pathogenesis.

DOI：
10.18632/oncotarget.25164
发表时间：
2018-04-24
期刊：
Oncotarget
影响因子：
0
作者：
Sager RA;Woodford MR;Shapiro O;Mollapour M;Bratslavsky G
通讯作者：
Bratslavsky G

Structure and function of the co-chaperone protein phosphatase 5 in cancer.

癌症中辅助伴侣蛋白磷酸酶 5 的结构和功能。

DOI：
10.1007/s12192-020-01091-3
发表时间：
2020
期刊：
Cell stress & chaperones
影响因子：
3.8
作者：
Sager,RebeccaA;Dushukyan,Natela;Woodford,Mark;Mollapour,Mehdi
通讯作者：
Mollapour,Mehdi

Phosphorylation and Ubiquitination Regulate Protein Phosphatase 5 Activity and Its Prosurvival Role in Kidney Cancer.

DOI：
10.1016/j.celrep.2017.10.074
发表时间：
2017-11-14
期刊：
Cell reports
影响因子：
8.8
作者：
Dushukyan N;Dunn DM;Sager RA;Woodford MR;Loiselle DR;Daneshvar M;Baker-Williams AJ;Chisholm JD;Truman AW;Vaughan CK;Haystead TA;Bratslavsky G;Bourboulia D;Mollapour M
通讯作者：
Mollapour M

The mTOR Independent Function of Tsc1 and FNIPs.