Rheb GTPase as chemotherapeutic target for brain tumors

Rheb GTPase 作为脑肿瘤化疗靶点

基本信息

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通常与脑肿瘤的恶性进展相关。 这种脂质磷酸酶在调节PI 3 K/Akt信号传导中发挥关键作用,PI 3 K/Akt信号传导通过TSC 2激活mTOR/S6 K途径。 我们最近确定了TSC 2肿瘤抑制因子作为Ras样GTdR,Rheb的GAP(GTdR激活蛋白;关闭开关),并证明Rheb激活mTOR/S6 K通路。 这表明,在PTEN或TSC 2丢失时,Rheb将变得组成性激活。 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是法尼基化的,其生物活性被先前设计用于阻断Ras作用的法尼基转移酶抑制剂(FTIs)抑制。 我们的中心假设是,由于PTEN丢失导致的Rheb活性失调,促进了异常细胞生长,从而导致肿瘤进展。 我们进一步提出,这种转化活性可以减弱FTIs。 为了验证这一假设,在目的1中,我们将证明显性抑制性Rheb突变体、Rheb RNAi和FTIs可以抑制S6激酶活化和人胶质瘤细胞的增殖。 在目标2中,我们将使用异种移植物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Rheb相关的GTdR,Rheb 2,是否类似地受到TSC 2和GEF的调节,以及它是否以类似于Rheb的方式发挥作用。 这些研究将为Rheb激活机制及其在细胞生长调节/肿瘤发生中的作用提供有价值的新信息。 他们将解决FTIs的非Ras作用的分子基础,并证明靶向Rheb在癌症治疗中的价值。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

LAWRENCE A. QUILLIAM其他文献

LAWRENCE A. QUILLIAM的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('LAWRENCE A. QUILLIAM', 18)}}的其他基金

Rheb GTPase as chemotherapeutic target for brain tumors
Rheb GTPase 作为脑肿瘤化疗靶点
  • 批准号:
    7574533
  • 财政年份:
    2005
  • 资助金额:
    $ 22.46万
  • 项目类别:
Rheb GTPase as chemotherapeutic target for brain tumors
Rheb GTPase 作为脑肿瘤化疗靶点
  • 批准号:
    7052093
  • 财政年份:
    2005
  • 资助金额:
    $ 22.46万
  • 项目类别:
Rheb GTPase as chemotherapeutic target for brain tumors
Rheb GTPase 作为脑肿瘤化疗靶点
  • 批准号:
    6921056
  • 财政年份:
    2005
  • 资助金额:
    $ 22.46万
  • 项目类别:
Rheb GTPase as chemotherapeutic target for brain tumors
Rheb GTPase 作为脑肿瘤化疗靶点
  • 批准号:
    7194998
  • 财政年份:
    2005
  • 资助金额:
    $ 22.46万
  • 项目类别:
REGULATION OF THE RAS TRANSFORMATION PATHWAY
RAS 转化途径的调节
  • 批准号:
    2104809
  • 财政年份:
    1994
  • 资助金额:
    $ 22.46万
  • 项目类别:
REGULATION OF THE RAS TRANSFORMATION PATHWAY
RAS 转化途径的调节
  • 批准号:
    2429802
  • 财政年份:
    1994
  • 资助金额:
    $ 22.46万
  • 项目类别:
REGULATION OF THE RAS TRANSFORMATION PATHWAY
RAS 转化途径的调节
  • 批准号:
    2104808
  • 财政年份:
    1994
  • 资助金额:
    $ 22.46万
  • 项目类别:
REGULATION OF THE RAS TRANSFORMATION PATHWAY
RAS 转化途径的调节
  • 批准号:
    2104807
  • 财政年份:
    1994
  • 资助金额:
    $ 22.46万
  • 项目类别:
REGULATION OF THE RAS TRANSFORMATION PATHWAY
RAS 转化途径的调节
  • 批准号:
    2104805
  • 财政年份:
    1994
  • 资助金额:
    $ 22.46万
  • 项目类别:
REGULATION OF THE RAS TRANSFORMATION PATHWAY
RAS 转化途径的调节
  • 批准号:
    2712687
  • 财政年份:
    1994
  • 资助金额:
    $ 22.46万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 22.46万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了