TUMOR SUPPRESSOR LIKE ACTIVITY OF ESTROGEN RECEPTOR

雌激素受体的肿瘤抑制样活性

• 批准号: 6498064
• 负责人: SAMUEL C BROOKS
• 金额: $ 22.35万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6498064
• 关键词: breast neoplasms; estrogen receptors; gene mutation; glutathione transferase; molecular cloning; northern blottings; oncoproteins; p53 gene /protein; protein protein interaction; reporter genes; site directed mutagenesis; tissue /cell culture; ubiquitin; western blottings

DESCRIPTION: (Adapted from the applicant's abstract): Recent evidence from the literature and from the applicant's laboratory points toward the physical interaction of estrogen receptor-a (ERa), p53 and hdm2. There are a number of ramifications, real and hypothesized, of this phenomenon. First, p53 down-regulates estradiol (E2)-responsive genes by interfering with the binding of ERa to ERE. Second, ERa in this ternary complex appears to bring about the protection of p53 transcriptional activity from being deactivated by hdm2. Third, this interplay could result in hdm2 regulation of ERa turnover. And fourth, as a consequence, regulated ERa expression may be a method of cellular control of p53 function. Employing transient and stable cell transfections, site directed mutagenesis, GST pull down methodology, ubiquitination assays, and reporter gene transcription assays, studies will be designed to address the following specific aims: Determine the residues involved in mediating the ERa-p53 and ERa-hdm2 binding in order to identify specific mutants of these regulatory proteins useful in examining the biological consequences of these interactions. Examine the biological consequences of the ERa-p53 interaction in breast cancer cells. Examine the functional consequences of the ERa-hdm2 interaction. Explore the possibility that ERbeta performs a function similar to ERa in this regulatory system. These studies will further develop the recently elucidated role of the unliganded ERa in the protection of the tumor suppressor p53 from deactivation by the oncogene hdm2. This tumor suppressor-like activity of ERa is a novel role for the estrogen receptor separate from its classic regulatory function as a ligand inducible transcription factor. The practical significance of these phenomena may be that the ERa-p53 binding protects breast epithelial and endometrial cells from hyperproliferation, which could contribute to malignant transformation, and the interaction of receptor with p53 mutants may play a role in the acquisition of hormone independence by ER positive breast cancer cells.

描述：（根据申请人的摘要改编）： 文学和申请人的实验室指向身体 雌激素受体A（ERA），p53和HDM2的相互作用。有很多 这种现象的真实和假设的后果。首先，p53 通过干扰结合，下调雌二醇（E2）响应基因 时代。第二，这个三元建筑群的时代似乎带来了 保护p53转录活性免受HDM2失活的保护。 第三，这种相互作用可能导致HDM2对ERA流失的调节。和 因此，第四，调节的ERA表达可能是细胞的一种方法 控制p53功能。采用瞬态和稳定的细胞转染， 站点定向诱变，GST下降方法，泛素化测定法， 和记者基因转录测定法，研究将旨在解决 遵循特定目的： 确定介导ERA-P53和ERA-HDM2绑定所涉及的残留物 为了确定这些调节蛋白的特定突变体有用 检查这些相互作用的生物学后果。 检查乳腺癌中ERA-P53相互作用的生物学后果 细胞。 检查ERA-HDM2相互作用的功能后果。 探索Erbeta执行与ERA相似的功能的可能性 监管系统。 这些研究将进一步发展最近阐明的作用 保护肿瘤抑制p53免于失活的无物时代 由ONCOGENE HDM2。这种抑制时代的肿瘤抑制作用是一种新颖 雌激素受体与其经典调节功能分开的作用 配体诱导转录因子。这些的实际意义 现象可能是ERA-P53结合保护乳房上皮和 超增殖的子宫内膜细胞，这可能导致恶性肿瘤 转化，受体与p53突变体的相互作用可能会播放 通过ER阳性乳腺癌获得激素独立性的作用 细胞。