Cables role in endometrial differentiation and cancer

电缆在子宫内膜分化和癌症中的作用

• 批准号: 7101809
• 负责人: Bo R. RUEDA
• 金额: $ 37.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7101809
• 关键词: cell cycle proteins; cell differentiation; cell growth regulation; cell proliferation; clinical research; endometrium; female; gene expression; gene induction /repression; genetically modified animals; hormone regulation /control mechanism; human tissue; laboratory mouse; neoplasm /cancer genetics; neoplastic transformation; progesterone; sex cycle; uterus neoplasms; uterus preneoplastic state

DESCRIPTION (provided by applicant): Endometrial cancer (EC) is the most common gynecologic malignancy in the United States and is believed in most cases to be related to overexposure to unopposed estrogens. EC is usually curable with surgery. Alternatively, progesterone, a natural inhibitor of cellular proliferation of the endometrium, has been used with limited success for endometrial hyperplasia or EC in patients who are concerned about fertility. The mechanisms of progesterone action, however, have yet to be defined. Progesterone can influence regulatory components of the cell cycle (e.g. cyclins, cyclin dependent kinases; cdks). Our recent studies have demonstrated that Cables, a novel cell cycle regulatory protein, is lost at a high frequency in EC. Cables appears to act as a linker protein, which facilitates tyrosine 15 phosphorytation of some cdks by non-receptor tyrosine kinases. Cdk2 regulates the G1 S-phase transition of the cell cycle and cdk2 tyrosine phosphorylation is inhibitory and leads to decreased cdk2 activity and slows cell growth. Cables enhances this inhibitory phosphorylation, so loss of Cables should result in increased, and possibly uncontrolled, cell growth. Progesterone appears to transcriptionally regulate Cables in epithelial cells derived from proliferating endometrium, but not in EC cell lines. More interesting, the Cables deficient mice have evidence of endometrial hyperplasia at 3 months of age and as such appears to be a mouse model that mimics the human disease. Collectively, these data have led us to hypothesize that Cables expression in normal endometrial epithelium is hormonally regulated, and Cables is absent or tess effective in transformed/transforming cells. Furthermore, we believe that a loss, or a reduced level of, Cables leads to atypical endometrial hyperptasia and/or neoplasia. To test our hypotheses, we have proposed the following aims 1) Determine the role of progesterone in mediating Cables induced inhibition of endometrial cell proliferation in vitro, 2) Determine if Cables is required for the anti-proliferative effects of progesterone in endometrial cells, and if loss of Cables facilitates EC development in vivo, 3) Investigate the endometrial changes associated with proliferation and differentiation during the estrous cycle and abnormal endometrial growth in Cables deficient mice, 4) Determine the mechanism of Cables gene inactivation in primary :human EC. The studies in this proposal will help determine the: role of Cables in I normal and malignant endometrial epithelium.

描述(申请人提供)：子宫内膜癌(EC)是美国最常见的妇科恶性肿瘤，在大多数情况下被认为与过度暴露于未对抗的雌激素有关。EC通常可以通过手术治愈。或者，孕酮，一种天然的子宫内膜细胞增殖抑制剂，已经被用于治疗子宫内膜增生症或关注生育能力的患者的EC，但效果有限。然而，黄体酮的作用机制尚未明确。黄体酮可以影响细胞周期的调节成分(如细胞周期蛋白、细胞周期蛋白依赖性蛋白激酶；CDKs)。我们最近的研究表明，CABLES是一种新的细胞周期调节蛋白，在EC中以很高的频率丢失。CABLES似乎扮演着连接蛋白的角色，它通过非受体酪氨酸激酶促进某些CDK的酪氨酸15磷酸化。CDK2调节细胞周期的G1-S期转变，而CDK2酪氨酸磷酸化受到抑制，导致CDK2活性降低，从而减缓细胞生长。线缆加强了这种抑制的磷酸化，因此线缆的缺失应该会导致细胞生长增加，甚至可能失控。孕酮似乎在转录水平上调节子宫内膜上皮细胞中的电缆，但在EC细胞系中不起作用。更有趣的是，电缆缺陷的小鼠在3个月大时就有子宫内膜增生的证据，因此似乎是一个模仿人类疾病的小鼠模型。总之，这些数据使我们假设CABLES在正常子宫内膜上皮中的表达是受激素调节的，并且CABLES在转化/转化细胞中缺失或TESS有效。此外，我们认为电缆的丢失或减少会导致不典型的子宫内膜肥大和/或肿瘤。为了验证我们的假设，我们提出了以下目标：1)确定孕酮在CABLE诱导的体外抑制子宫内膜细胞增殖中的作用；2)确定CABLE是否是孕酮抗子宫内膜细胞增殖作用所必需的，以及CABLE的丢失是否促进了在体EC的发育；3)研究CABLE缺陷小鼠动情周期中与增殖和分化相关的子宫内膜变化和子宫内膜的异常生长；4)确定CABLE基因在原代培养的人EC中失活的机制。该方案中的研究将有助于确定电缆在正常和恶性子宫内膜上皮中的作用。