Role of Km23 in Ovarian Cancer

Km23 在卵巢癌中的作用

• 批准号: 6889653
• 负责人: Kathleen M Mulder
• 金额: $ 33.31万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889653
• 关键词: athymic mouse; biological signal transduction; cell line; chimeric proteins; clinical research; dynein ATPase; fluorescence resonance energy transfer; growth factor receptors; human tissue; intermediate filaments; laser capture microdissection; matrix assisted laser desorption ionization; mutant; neoplasm /cancer classification /staging; neoplasm /cancer genetics; nucleic acid purification; ovary neoplasms; phenotype; phosphorylation; protein kinase C; protein protein interaction; protein structure function; receptor expression; site directed mutagenesis; transforming growth factors; tumor suppressor proteins

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）：卵巢癌在超过80%的患者中出现在晚期临床阶段，其与35%的5年存活率相关。因此，非常需要开发用于卵巢癌的治疗和预后的更有希望的药剂。已知TGF β是一种肿瘤抑制因子，介导其生物学效应的细胞内组分也可以以这种方式发挥作用。此外，对TGF β的生长抑制作用的抗性发生在大约75%的卵巢癌病例中，特别是复发性疾病。我们已经确定了一种新的TGF β信号传导成分，称为km23，这也是一个轻链的马达蛋白动力蛋白。这种细胞质组分与TGF β受体相互作用，并在TGF β受体活化后磷酸化。此外，km23的表达介导特异性TGF β反应，包括上皮细胞的生长抑制。此外，我们已经在11个人类患者的上皮性卵巢癌中的4个中以及在33%的人类卵巢癌细胞（HOCC）系中鉴定了km23的改变。由于km23似乎是在人卵巢癌中改变的TGF β信号传导组分，我们假设TGF β敏感性HOCC中“肿瘤样”km23改变的表达将抑制TGF β抑制这些细胞生长的能力，该提案的总体目标是确定在卵巢癌患者中鉴定的km23改变是否会导致TGF β控制的生长改变，体外表型转化更多，体内致瘤性增加。我们还将扩展对人类癌症组织的分析，以确定发生变化的疾病频率和阶段，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，我们将确定确切的域之间的相互作用公里23和中间链的马达蛋白动力蛋白，并确定如何改变公里23影响这种相互作用。我们假设后两种类型的研究将有助于筛选出治疗卵巢癌的新药物