Rheb GTPase as chemotherapeutic target for brain tumors

Rheb GTPase 作为脑肿瘤化疗靶点

基本信息

批准号：
7052093
负责人：
LAWRENCE A. QUILLIAM
金额：
$ 23.13万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-11 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7052093
关键词：
alkyltransferase antineoplastics athymic mouse brain neoplasms cell growth regulation cell line enzyme activity enzyme induction /repression enzyme inhibitors guanine nucleotide exchange factors guanosinetriphosphatase activating protein guanosinetriphosphatases human tissue neoplastic growth phosphomonoesterases prenylation

项目摘要

DESCRIPTION (provided by applicant): Loss of the PTEN tumor suppressor is frequently associated with the malignant progression of brain tumors. This lipid phosphatase plays a key role in regulating PI3K/Akt signaling which, through TSC2, activates the mTOR/S6K pathway. We recently identified the TSC2 tumor suppressor as a GAP (GTPase activating protein; off switch) for the Ras-like GTPase, Rheb, and demonstrated that Rheb activates the mTOR/ S6K pathway. This suggested that upon PTEN or TSC2 loss, Rheb will become constitutively activated. Indeed, we find Rheb-GTP levels are halved upon re-expression of PTEN in PTEN-deficient glioblastoma cells. Interestingly, Rheb is farnesylated and its biological activity is inhibited by the farnesyl transferase inhibitors (FTIs) previously designed to block Ras action. Our central hypothesis is that deregulated Rheb activity, resulting from PTEN loss, promotes abnormal cell growth that contributes to tumor progression. We further propose that this transforming activity can be attenuated by FTIs. To test this hypothesis, in Aim 1, we will demonstrate that dominant inhibitory Rheb mutants, Rheb RNAi and FTIs can inhibit S6 kinase activation and the proliferation of human glioma cells. In Aim 2, we will use xenograft and intracranial mouse tumor models to determine the ability of these approaches to inhibit tumor growth. In Aim 3, we will use our established assays to identify the guanine nucleotide exchange factor (GEF) responsible for turning Rheb on. Identification of this GEF and the pathway that regulates it will provide a better understanding of Rheb's cellular function and identify additional avenues to disrupt its activity. We will also determine if the Rheb-related GTPase, Rheb2, is similarly regulated by TSC2 and GEFs and if it functions in a similar manner to Rheb. Together these studies will provide valuable new information on the mechanisms of Rheb activation and its role in cell growth regulation/ tumorigenesis. They will address the molecular basis of non-Ras action of FTIs and demonstrate the value of targeting Rheb in cancer therapy.

描述（由申请人提供）：PTEN肿瘤抑制因子的缺失常常与脑肿瘤的恶性进展相关。这种脂质磷酸酶在调节 PI3K/Akt 信号传导中发挥着关键作用，PI3K/Akt 信号传导通过 TSC2 激活 mTOR/S6K 通路。我们最近将 TSC2 肿瘤抑制因子鉴定为 Ras 样 GTP 酶 Rheb 的 GAP（GTP 酶激活蛋白；关闭开关），并证明 Rheb 激活 mTOR/S6K 通路。这表明在 PTEN 或 TSC2 丢失后，Rheb 将被组成型激活。事实上，我们发现在 PTEN 缺陷的胶质母细胞瘤细胞中重新表达 PTEN 后，Rheb-GTP 水平减半。有趣的是，Rheb 被法尼基化，其生物活性受到先前设计用于阻断 Ras 作用的法尼基转移酶抑制剂 (FTI) 的抑制。我们的中心假设是，PTEN 缺失导致 Rheb 活性失调，促进异常细胞生长，从而导致肿瘤进展。我们进一步建议 FTI 可以减弱这种转化活动。为了检验这一假设，在目标 1 中，我们将证明显性抑制性 Rheb 突变体、Rheb RNAi 和 FTI 可以抑制 S6 激酶激活和人神经胶质瘤细胞的增殖。在目标 2 中，我们将使用异种移植和颅内小鼠肿瘤模型来确定这些方法抑制肿瘤生长的能力。在目标 3 中，我们将使用我们已建立的检测方法来鉴定负责开启 Rheb 的鸟嘌呤核苷酸交换因子 (GEF)。鉴定该 GEF 及其调节途径将有助于更好地了解 Rheb 的细胞功能，并确定破坏其活性的其他途径。我们还将确定与 Rheb 相关的 GTP 酶 Rheb2 是否受到 TSC2 和 GEF 的类似调节，以及它是否以与 Rheb 类似的方式发挥作用。这些研究将共同提供关于 Rheb 激活机制及其在细胞生长调节/肿瘤发生中的作用的有价值的新信息。他们将探讨 FTI 非 Ras 作用的分子基础，并证明靶向 Rheb 在癌症治疗中的价值。