Role of Km23 in Ovarian Cancer

Km23 在卵巢癌中的作用

基本信息

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer presents at a late clinical stage in more than 80% of patients It is associated with a 5-year survival rate of 35% Thus, there is a great need to develop more promising agents for the treatment and prognosis of ovarian cancer. TGFbeta is known to be a tumor suppressor, and intracellular components that mediate its biological effects can also function in this manner. Further, resistance to the growth inhibitory effects of TGFbeta occurs in approximately 75% of ovarian cancer cases, especially with recurrent disease. We have identified a novel TGFbeta signaling component, termed km23, which is also a light chain of the motor protein dynein. This cytoplasmic component interacts with the TGFbeta receptors and is phosphorylated upon TGFbeta receptor activation. Further, expression of km23 mediates specific TGFbeta responses, including growth inhibition of epithelial cells Moreover, we have identified alterations in km23 in 4 out of 11 epithelial ovarian cancers from human patients, and in 33% of human ovarian cancer cell (HOCC) lines. Since km23 appears to be a TGFbeta signaling component that is altered in human ovarian cancer, we hypothesize that expression of the "tumor-like" km23 alterations in TGFbeta-sensitive HOCCs will suppress the ability of TGFbeta to inhibit the growth of these cells, and produce a more malignant phenotype The overall goal of this proposal is to determine whether the km23 alterations identified in ovarian cancer patients will result in altered growth control by TGFbeta, a more transformed phenotype in vitro, and increased tumorigenicities in vivo. We will also extend our analyses of human cancer tissues to determine the frequency and stage of disease at which the changes occur, as well as the frequency in the normal population. Additional studies will identify the kinase that phosphorylates km23, as well as the precise km23 phosphorylation sites. Finally, we will identify the exact domains of interaction between km23 and the intermediate chain of the motor protein dynein, and determine how alterations in km23 affect this interaction. We hypothesize that the latter two types of studies will assist in the development of screens by which to identify novel agents for the treatment of ovarian cancer
描述(由申请人提供):超过80%的卵巢癌患者出现在临床晚期,与35%的5年生存率相关,因此非常需要开发更有前景的卵巢癌治疗和预后药物。tgf β是一种已知的肿瘤抑制因子,介导其生物效应的细胞内成分也可以以这种方式起作用。此外,在大约75%的卵巢癌病例中,特别是复发性卵巢癌病例中,出现了对tgf - β生长抑制作用的耐药性。我们已经确定了一种新的tgf β信号成分,称为km23,它也是运动蛋白动力蛋白的轻链。这种细胞质成分与tgfβ受体相互作用,并在tgfβ受体激活时磷酸化。此外,km23的表达介导特异性TGFbeta反应,包括上皮细胞的生长抑制。此外,我们已经在11例人类上皮性卵巢癌患者中的4例和33%的人类卵巢癌细胞(HOCC)系中发现了km23的改变。由于km23似乎是在人类卵巢癌中发生改变的tgf β信号成分,我们假设在tgf β敏感的hocc中表达“肿瘤样”km23改变将抑制tgf β抑制这些细胞生长的能力,并产生更恶性的表型。本建议的总体目标是确定卵巢癌患者中发现的km23改变是否会导致tgf β对生长控制的改变。在体外更转化的表型,并增加体内的致瘤性。我们还将扩展我们对人类癌症组织的分析,以确定发生变化的频率和疾病阶段,以及正常人群的频率。进一步的研究将确定磷酸化km23的激酶,以及精确的km23磷酸化位点。最后,我们将确定km23和马达蛋白动力蛋白中间链之间相互作用的确切区域,并确定km23的改变如何影响这种相互作用。我们假设后两种类型的研究将有助于开发筛选,以确定卵巢癌治疗的新药物

项目成果

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Kathleen M Mulder其他文献

Kathleen M Mulder的其他文献

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{{ truncateString('Kathleen M Mulder', 18)}}的其他基金

Directional Motility and ERM Scaffolding in Pathfinder Pancreatic Carcinoma Cells
Pathfinder 胰腺癌细胞的定向运动和 ERM 支架
  • 批准号:
    8779713
  • 财政年份:
    2014
  • 资助金额:
    $ 31.58万
  • 项目类别:
Role of TGFbeta in Microtubule Dynamics
TGFbeta 在微管动力学中的作用
  • 批准号:
    7915833
  • 财政年份:
    2009
  • 资助金额:
    $ 31.58万
  • 项目类别:
Mechanisms of TGF-Beta Production in Human Cancer Cells
人类癌细胞中 TGF-β 产生的机制
  • 批准号:
    8073200
  • 财政年份:
    2007
  • 资助金额:
    $ 31.58万
  • 项目类别:
Mechanisms of TGF-Beta Production in Human Cancer Cells
人类癌细胞中 TGF-β 产生的机制
  • 批准号:
    7472603
  • 财政年份:
    2007
  • 资助金额:
    $ 31.58万
  • 项目类别:
Mechanisms of TGF-Beta Production in Human Cancer Cells
人类癌细胞中 TGF-β 产生的机制
  • 批准号:
    7841799
  • 财政年份:
    2007
  • 资助金额:
    $ 31.58万
  • 项目类别:
Mechanisms of TGF-Beta Production in Human Cancer Cells
人类癌细胞中 TGF-β 产生的机制
  • 批准号:
    7628570
  • 财政年份:
    2007
  • 资助金额:
    $ 31.58万
  • 项目类别:
Mechanisms of TGF-Beta Production in Human Cancer Cells
人类癌细胞中 TGF-β 产生的机制
  • 批准号:
    7321536
  • 财政年份:
    2007
  • 资助金额:
    $ 31.58万
  • 项目类别:
Role of Km23 in Ovarian Cancer
Km23 在卵巢癌中的作用
  • 批准号:
    7034466
  • 财政年份:
    2003
  • 资助金额:
    $ 31.58万
  • 项目类别:
Role of Km23 in Ovarian Cancer
Km23 在卵巢癌中的作用
  • 批准号:
    6599167
  • 财政年份:
    2003
  • 资助金额:
    $ 31.58万
  • 项目类别:
Role of Km23 in Ovarian Cancer
Km23 在卵巢癌中的作用
  • 批准号:
    6889653
  • 财政年份:
    2003
  • 资助金额:
    $ 31.58万
  • 项目类别:

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