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(申请人提供)：卵巢癌在超过80%的患者中处于临床晚期，它与35%的5年生存率有关，因此，迫切需要开发更有前途的药物来治疗和预后卵巢癌。众所周知，TGFbeta是一种肿瘤抑制因子，介导其生物学效应的细胞内成分也可以通过这种方式发挥作用。此外，大约75%的卵巢癌患者，尤其是复发的卵巢癌患者，会对转化生长因子β的生长抑制作用产生抵抗。我们已经确定了一个新的TGFbeta信号成分，命名为km23，它也是运动蛋白dynein的轻链。这种细胞质成分与转化生长因子β受体相互作用，并在转化生长因子β受体激活时被磷酸化。此外，km23的表达介导了特异性的转化生长因子β反应，包括对上皮细胞的生长抑制。此外，我们已经在11例人卵巢上皮癌中发现了4例km23的改变，并在33%的人卵巢癌细胞(HOCC)株中发现了km23的改变。由于km23似乎是一种在人类卵巢癌中发生改变的TGFbeta信号成分，我们假设在对TGFbeta敏感的HOCC中“肿瘤样”km23改变的表达将抑制TGFbeta抑制这些细胞的生长的能力，并产生更恶性的表型。这项建议的总体目标是确定在卵巢癌患者中发现的km23改变是否会导致TGFbeta的生长控制改变，这是一种在体外更具转化的表型，并增加体内的肿瘤原性。我们还将扩展我们对人类癌症组织的分析，以确定这些变化发生的疾病频率和阶段，以及正常人群的频率。更多的研究将确定使km23磷酸化的激酶，以及准确的km23磷酸化位点。最后，我们将确定km23和运动蛋白dynein中间链之间相互作用的确切结构域，并确定km23的变化如何影响这种相互作用。我们推测，后两种类型的研究将有助于筛选出治疗卵巢癌的新药物。