Estrogen Receptor, MTA3, and Transcriptional Repression

雌激素受体、MTA3 和转录抑制

• 批准号: 6709533
• 负责人: PAUL A WADE
• 金额: $ 26.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6709533
• 关键词: breast neoplasms; chromatin; estrogen receptors; estrogens; gene induction /repression; genetic promoter element; genetic transcription; histones; hormone regulation /control mechanism; microarray technology; neoplasm /cancer genetics; oncoproteins; protein protein interaction; receptor binding; tissue /cell culture; transfection; breast neoplasms; chromatin; estrogen receptors; estrogens; gene induction /repression; genetic promoter element; genetic transcription; histones; hormone regulation /control mechanism; microarray technology; neoplasm /cancer genetics; oncoproteins; protein protein interaction; receptor binding; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): In the US, breast cancer accounts for roughly 30% of all cancers in females and is the second leading cause of cancer deaths in women. For many years, the estrogen receptor has been recognized as a critical determinant of breast epithelial cell physiology, as an important clinical prognostic indicator and as an attractive target for chemotherapy in breast cancers. Humans have two classes of estrogen receptor; both exert their biological effects by directly activating transcription of specific target genes. Like all transcriptional regulators, estrogen receptor action leads to primary effects by stimulating the expression of direct target genes and also to secondary effects mediated by the biological action of direct transcriptional targets of the receptor. The downstream regulatory networks elicited by the transcriptional targets of ER constitute an important component of estrogen action. I propose to investigate a novel gene regulatory pathway constituting a secondary effect of estrogen receptor activation. We will investigate the novel human protein MTA3, a member of the MTA (metastasis associated protein) gene family. Our working hypothesis proposes that MTA3, like its well-characterized relatives MTA1 and MTA2, constitutes an integral subunit of the histone deacetylase containing transcriptional corepressor complex known as Mi2/NuRD. Preliminary characterization of MTA family members in breast cancer cell lines has determined that MTA3 expression is completely dependent on estrogen receptor function. In addition, our preliminary data indicate that MTA3 functions in a novel gene regulatory pathway that regulates invasive growth properties of estrogen-responsive cancer cell lines. I now propose to study MTA3 and its action through three specific aims. Specific Aim 1 will characterize the MTA3 gene and its transcriptional regulation by estrogens. Specific Aim 2 will provide a detailed biochemical characterization of the Mi2/NuRD complex in estrogen responsive cells with particular emphasis on changes in properties and/or subunit composition resulting from estrogen receptor action. Specific Aim 3 will identify and characterize the cohort of genes directly regulated by MTA3 using both systematic and candidate approaches. The ultimate goals of this project are (1) to provide a more complete description of the genetic program downstream of estrogen receptor and (2) to understand the contribution(s) of MTA3 to prevention of invasive and metastatic cell growth.

描述（由申请人提供）：在美国，乳腺癌约占女性所有癌症的30％，是女性癌症死亡的第二大原因。多年来，雌激素受体一直被认为是乳腺上皮细胞生理学的关键决定因素，是重要的临床预后指标，也是乳腺癌化学疗法的有吸引力的靶标。人类有两类的雌激素受体。两者都通过直接激活特定靶基因的转录来发挥其生物学作用。像所有转录调节剂一样，雌激素受体的作用通过刺激直接靶基因的表达以及受受体直接转录靶标的生物学作用介导的次级作用而导致主要作用。 ER的转录靶标引起的下游调节网络构成了雌激素作用的重要组成部分。我建议研究一种新的基因调节途径，构成雌激素受体激活的次要作用。我们将研究新型的人类蛋白MTA3，这是MTA（转移相关蛋白）基因家族的成员。我们的工作假设提出，MTA3与其特征良好的亲戚MTA1和MTA2一样，构成了组蛋白脱乙酰基酶的整体亚基，该子蛋白含有转录核心压轴络合物，称为MI2/NURD。 MTA家族成员在乳腺癌细胞系中的初步表征确定MTA3表达完全取决于雌激素受体功能。此外，我们的初步数据表明，MTA3在新的基因调节途径中起作用，该途径调节雌激素反应性癌细胞系的侵入性生长特性。我现在建议通过三个特定目标研究MTA3及其行动。特定的目标1将表征MTA3基因及其通过雌激素的转录调节。具体目标2将提供雌激素反应细胞中MI2/NURD复合物的详细生化表征，并特别强调雌激素受体作用引起的性质和/或亚基组成的变化。特定的目标3将使用系统和候选方法识别并表征由MTA3直接调节的基因的队列。该项目的最终目标是（1）提供对雌激素受体下游的遗传程序的更完整描述，以及（2）了解MTA3对预防侵入性和转移性细胞生长的贡献。