Protein prenylation, oncogenesis and novel therapeutics

蛋白质异戊二烯化、肿瘤发生和新疗法

• 批准号: 6948887
• 负责人: ADRIENNE D COX
• 金额: $ 23.78万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/6948887
• 关键词: SDS polyacrylamide gel electrophoresis; alkyltransferase; antineoplastics; athymic mouse; carcinogenesis; enzyme activity; enzyme inhibitors; enzyme mechanism; guanine nucleotide binding protein; isoprenoid; prenylation; protein structure function; protein tyrosine phosphatase; tumor suppressor proteins; western blottings

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）：我们研究的一个主要目标是描述蛋白质异戊二烯化在促进Ras和Rhc GTP酶介导的肿瘤发生中的作用。从这些研究中，出现了三大主题。首先，Ras和Rho GT3功能的异常激活对人类肿瘤发生的许多方面都有重要贡献。第二，虽然最初认为蛋白质的类异戊二烯脂质修饰只是作为疏水性的、非特异性的膜靶向脂质“胶”，但我们现在认识到异戊二烯化与其他序列元件和脂质修饰一起决定了动态膜相互作用的复杂谱，其赋予否则高度相关的GTP酶显著不同的生物学作用。第三，由于Ras和Rho GT3膜的结合和功能严重依赖于类异戊二烯修饰，因此蛋白质异戊二烯化的药理学抑制可能是癌症治疗的有效方法。催化Ras和Rho GTP酶的异戊二烯化的酶的抑制剂已被开发为新颖的基于靶点的疗法。特别是，修饰Ras蛋白的酶法尼基转移酶（FTase）的抑制剂（FTIs）在临床前模型中显示出显著的抗肿瘤活性，目前正在进行II-III期临床评价。令人惊讶的是，现在接受的是，FTI的抗肿瘤活性不是由于Ras抑制。相反，FTI的关键靶标被认为是其他FTase底物。确定这些关键的FTI目标对于FTI的成功临床开发至关重要。我们提出了从这三个主题延伸的四个具体目标。首先，我们将定义新的机制，Cdc 42相关的蛋白质的C-末端序列，Cdc 42，Cdc 42 -1和Cdc 42 -2/Chp，支配膜协会和功能多样性。出乎意料的是，这两种Rho GTP酶不是使其它Ras和Rho GTP酶异戊二烯化的FTase或GGT酶I的底物。其次，我们将确定法尼基化的GTdR-Rheb（最近通过激活mTOR/S6激酶途径参与肿瘤发生）是否被FTIs靶向。第三，我们将确定FTI介导的法尼基化Ras相关肿瘤抑制蛋白NOEY 2/ARHI和Rig/Di-Ras的丢失是否定义了FTI治疗的潜在有害后果。最后，我们将确定参与促进肿瘤细胞侵袭和转移的PRL蛋白酪氨酸磷酸酶是否是FTI抗肿瘤活性的重要靶点。