Protein prenylation, oncogenesis and novel therapeutics

蛋白质异戊二烯化、肿瘤发生和新疗法

基本信息

批准号：
7286068
负责人：
ADRIENNE D COX
金额：
$ 22.55万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-14 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7286068
关键词：
Adverse effects Affect Biological C-terminal Cell membrane Chronic Class Clinic Clinical Complex Cytostatics Development Elements Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Family Farnesyl Transferase Inhibitor Geranylgeranyltransferase type II Glues Goals Growth Guanosine Triphosphate Phosphohydrolases Human Lipids Localized Mediating Membrane Mitosis Modification Monomeric GTP-Binding Proteins Neoplasm Metastasis Oncogenic Outcome PRL gene Pathway interactions Patient Selection Phase Phosphoric Monoester Hydrolases Phosphotransferases Post-Translational Protein Processing Pre-Clinical Model Prolactin Property Protein Isoprenylation Protein Tyrosine Phosphatase Proteins RAS Superfamily Proteins Research Ribosomal Protein S6 Kinase Role Signal Transduction TSC1/2 gene Thinking Tumor Cell Invasion Tumor Suppressor Proteins anti-cancer therapeutic attenuation base cancer therapy cell growth farnesyltranstransferase human FRAP1 protein inhibitor/antagonist isoprenoid isoprenylation member next generation novel novel therapeutics palmitoylation prenylation protein farnesyltransferase protein geranylgeranyltransferase ras Proteins research clinical testing response rho rho GTP-Binding Proteins tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): A major goal of our research has been the delineation of the role of protein isoprenylation in facilitating Ras and Rhc GTPase-mediated oncogenesis. From these studies, three major themes have emerged. First, the aberrant activation of Ras and Rho GTPase function contributes significantly to many facets of human oncogenesis. Second, while it was initially believed that isoprenoid lipid modification of proteins served simply as hydrophobic, nonspecific membrane-targeting lipid "glues", we now appreciate that isoprenylation, together with other sequence elements and lipid modifications, dictate a complex spectrum of dynamic membrane interactions that endow otherwise highly related GTPases with strikingly divergent biological roles. Third, since Ras and Rho GTPase membrane association and function are critically dependent on isoprenoid modification, pharmacologic inhibition of protein prenylation may be an effective approach for cancer treatment. Inhibitors of the enzymes that catalyze the isoprenylation of Ras and Rho GTPases have been developed as novel, target-based therapies. In particular, inhibitors (FTIs) of the enzyme farnesyl transferase (FTase) that modifies Ras proteins have shown remarkable anti-tumor activity in preclinical models and are currently under phase II-III clinical evaluation. Surprisingly, it is now accepted that the anti-tumor activity of FTIs is not due to Ras inhibition. Instead, the critical targets of FTIs are thought to be other FTase substrates. Defining these critical FTI targets will be crucial for the successful clinical development of FTIs. We propose four specific aims that extend from these three themes. First, we will define the novel mechanism by which the C-terminal sequences of the Cdc42-related proteins, Wrch-1 and Wrch-2/Chp, dictate membrane association and functional diversity from Cdc42. Unexpectedly, these two Rho GTPases are not substrates for either the FTase or GGTase I enzyme that isoprenylates the other Ras and Rho GTPases. Second, we will determine whether the farnesylated GTPase Rheb, recently implicated in oncogenesis by activation of the mTOR/S6 kinase pathway, is targeted by FTIs. Third, we will determine whether FTI-mediated loss of the farnesylated, Ras-related tumor suppressor proteins NOEY2/ARHI and Rig/Di-Ras define a potentially deleterious consequence of FTI therapy. Finally, we will determine whether the PRL protein tyrosine phosphatases, involved in promoting tumor cell invasion and metastasis, are important targets of FTI antitumor activity.

描述（由申请人提供）：我们研究的主要目的是描述蛋白质异源肾上腺素在促进RAS和RHC GTPase介导的肿瘤发生中的作用。从这些研究中，出现了三个主要主题。首先，Ras和Rho GTPase功能的异常激活对人类肿瘤发生的许多方面显着贡献。其次，虽然最初认为蛋白质的异型脂质修饰只是用作疏水，非特异性膜靶向脂质的脂质“胶水”，但我们现在欣赏异源性元素的化以及其他序列元件以及脂质元素和脂质修饰，决定了动态膜相互作用的复杂谱，否则将其与高度相关的gtpass extiver confive gtppspass否定。第三，由于RAS和RHO GTPase膜的关联和功能在关键取决于类吸引的修饰，因此药物抑制蛋白质的蛋白质可能是癌症治疗的有效方法。催化Ras和Rho GTPases的异丙肾上腺素化的酶的抑制剂已被开发为基于靶基的新型疗法。特别是，修饰Ras蛋白的酶Farnesyl转移酶（FTase）的抑制剂（FTI）在临床前模型中显示出显着的抗肿瘤活性，目前处于II-IIII期临床评估中。令人惊讶的是，现在接受FTI的抗肿瘤活性不是由于RAS抑制作用。取而代之的是，FTI的关键目标被认为是其他FTase底物。定义这些关键的FTI目标对于FTI的成功临床发展至关重要。我们提出了从这三个主题延伸的四个特定目标。首先，我们将定义新的机制，通过该机制，CDC42相关蛋白的C末端序列，WRCH-1和WRCH-2/CHP决定了Cdc42的膜关联和功能多样性。出乎意料的是，这两个Rho GTPase不是Isoprenyls的FTase或GGTase I酶的底物，将其他RAS和Rho GTPase酶构成。其次，我们将确定FTIS的靶向是通过激活MTOR/S6激酶途径与最近与肿瘤发生有关的Farnesylaty GTPase RheB。第三，我们将确定FTI介导的FARNESYLED，与RAS相关的肿瘤抑制蛋白NOEY2/ARHI和RIG/DI-RAS的丧失是否定义了FTI治疗的潜在有害后果。最后，我们将确定与促进肿瘤细胞侵袭和转移有关的PRL蛋白酪氨酸磷酸酶是否是FTI抗肿瘤活性的重要靶标。