Roles of Novel Protein Complexes in Estrogen and Progesterone Receptor Signaling

新型蛋白质复合物在雌激素和孕激素受体信号传导中的作用

• 批准号: 8022886
• 负责人: Zafar Nawaz
• 金额: $ 32.45万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8022886
• 关键词: Affect; Animals; Attenuated; Binding; Biological; Biological Assay; Biology; Biopsy; Breast; Breast Cancer Model; Cell Line; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Chromosome Fragile Sites; Chromosomes; Collaborations; Complex; Confocal Microscopy; Cytoplasm; Data; Development; Diagnostic Neoplasm Staging; Disease; Estrogen Receptor 1; Estrogen Receptors; Event; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Growth; Health; Hereditary Disease; Hormone Receptor; Hormones; Human; Human Mammary Epithelium; In Vitro; Incidence; Inflammation; Inherited; Laboratories; Learning; Ligands; Loss of Heterozygosity; Lysine; Malignant Neoplasms; Mammary Neoplasms; Manuscripts; Measures; Mediating; Metabolic Diseases; Metabolism; Molecular; Molecular Profiling; Multiprotein Complexes; Mus; Mutation; Normal tissue morphology; Nuclear Hormone Receptors; Nuclear Receptor Coactivator 3; Oncogene Proteins; Oncogenic; Oxidoreductase; Pathogenesis; Pathologic Processes; Pathway interactions; Pattern; Physiological; Physiological Processes; Play; Progesterone Receptor Status; Progesterone Receptors; Protein Binding Domain; Proteins; Receptor Signaling; Relative (related person); Reproduction; Role; Source; Testing; Time; Transactivation; Transcription Coactivator; Transcriptional Activation; Transcriptional Activation Domain; Transcriptional Regulation; Tumor Suppressor Proteins; Tumor stage; Tumor-Derived; Tumorigenicity; Uncertainty; Work; attenuation; base; breast tumorigenesis; cancer type; cell growth; chromatin immunoprecipitation; chromatin modification; genetic regulatory protein; human UBE3A protein; in vivo; insight; malignant breast neoplasm; mouse model; mutant; neoplastic cell; novel; overexpression; polyproline; prevent; proline-rich proteins; promoter; protein complex; receptor; receptor function; steroid hormone receptor; transcription factor; tumor growth; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Estrogen receptor-1 (ER) and progesterone receptor (PR) are ligand-induced transcription factors. Accessory proteins, termed coactivators modulate the transcriptional activation of these factors. It has been shown that coactivators enhance transcription of the target genes and play important roles in diverse pathological processes, such as cancers, inherited genetic diseases, metabolic disorders, and inflammation. Earlier work by our laboratory identified E6-associated protein (E6-AP) as a coactivator of steroid hormone receptors. In an attempt to identify E6-AP-interacting protein(s), we have cloned WW-domain binding protein-2 (WBP-2) and have shown that WBP-2 selectively coactivates the transactivation functions of ER and PR. WBP-2 is a novel polyproline rich (PPXY) motif containing protein. The PPXY motif of WBP-2 has been shown to be involved in transcriptional activation pathways. The PPXY motif interacts with WW-domain containing proteins and form PPXY motif and WW-domain (PPXY-WW) complex and mediates transcription stimulation. The PPXY-WW module has gained prominence in the last decade and many new roles of the PPXY-WW complex in the nucleus, cellular pathways, physiological and pathological processes are just emerging. WW-domains have been observed on several key regulatory proteins like yes associated protein (YAP1) and WW-domain- containing oxidoreductase (WWOX1). YAP1 has been shown to act as transcriptional coactivator for several transcription factors and has also been classified as an oncoprotein, whereas, WWOX1 has been identified as a tumor suppressor. Our preliminary data suggest that oncogenic YAP1 in conjunction with WBP-2 enhances ER and PR signaling. This increased in ER and PR signaling is attenuated by the tumor suppressor WWOX1 but the exact mechanism by which these proteins regulate transcription, cell function, growth and tumorigenesis is largely unknown. In order to understand the mechanism of action of these proteins and their physiological and pathological relevance, we hypothesize that the coactivation functions of oncoprotein YAP1 is dependent on WBP-2 where the WBP-2:YAP1 complex enhances ER and PR transactivation functions resulting in breast tumorigenesis. We further hypothesize that WWOX1 acts as a tumor suppressor by physically blocking the formation of this complex (WBP-2:YAP1) resulting in the attenuation of their coactivation and oncogenic functions. This hypothesis will be test by the following specific aims: A) To determine the role of WW-domain containing proteins, YAP1 and WWOX1 in ER and PR-mediated gene transcription; B) To decipher the mechanism by which WBP-2, YAP1 and WWOX1 regulate ER and PR transactivation functions; and C) To determine the role of WBP-2, YAP1 and WWOX1 in breast tumorigenesis. PUBLIC HEALTH RELEVANCE: Estrogen and progesterone receptors are key regulatory proteins that affect many physiological and pathological processes such as reproduction, metabolism and cancer etc. Coactivators are proteins that regulate the functions of these receptor proteins and are also key players in the development of different types of cancers. Given these facts, the understanding of coactivator biology and their mechanism of action will be useful in developing new therapies.

描述（申请人提供）：雌激素受体-1（ER）和孕激素受体（PR）是配体诱导的转录因子。辅助蛋白，称为辅激活因子调节这些因子的转录激活。研究表明，共激活因子可促进靶基因的转录，在多种病理过程中发挥重要作用，如癌症、遗传性疾病、代谢紊乱和炎症等。我们实验室的早期工作确定了E6相关蛋白（E6-AP）作为类固醇激素受体的共激活剂。为了鉴定E6-AP相互作用蛋白，我们克隆了WW-domain binding protein-2（WBP-2），并证明WBP-2选择性地共激活ER和PR的反式激活功能。WBP-2的PPXY基序已被证明参与转录激活途径。PPXY基序与含有WW结构域的蛋白质相互作用，形成PPXY基序和WW结构域（PPXY-WW）复合物，并介导转录刺激。PPXY-WW模块在过去十年中获得了突出地位，PPXY-WW复合物在细胞核、细胞通路、生理和病理过程中的许多新作用正在出现。已经在几种关键的调节蛋白如yes相关蛋白（YAP 1）和含WW-domain的氧化还原酶（WWOX 1）上观察到了WW-domain。YAP 1已被证明是几种转录因子的转录共激活因子，也被归类为癌蛋白，而WWOX 1已被鉴定为肿瘤抑制因子。我们的初步数据表明，致癌YAP 1与WBP-2结合增强ER和PR信号。ER和PR信号的增加被肿瘤抑制因子WWOX 1减弱，但这些蛋白质调节转录、细胞功能、生长和肿瘤发生的确切机制在很大程度上是未知的。为了了解这些蛋白的作用机制及其生理和病理相关性，我们假设癌蛋白YAP 1的共激活功能依赖于WBP-2，其中WBP-2：YAP 1复合物增强ER和PR反式激活功能，导致乳腺肿瘤发生。我们进一步假设，WWOX 1作为一种肿瘤抑制因子，通过物理阻断这种复合物（WBP-2：YAP 1）的形成，导致其共激活和致癌功能的衰减。该假设将通过以下具体目的进行检验：A）确定含WW结构域的蛋白质、YAP 1和WWOX 1在ER和PR介导的基因转录中的作用; B）破译WBP-2、YAP 1和WWOX 1调节ER和PR反式激活功能的机制;和C）确定WBP-2、YAP 1和WWOX 1在乳腺肿瘤发生中的作用。公共卫生相关性：雌激素和孕激素受体是影响生殖、代谢和癌症等多种生理和病理过程的关键调节蛋白。辅激活因子是调节这些受体蛋白功能的蛋白质，也是不同类型癌症发生的关键参与者。鉴于这些事实，了解辅激活因子生物学及其作用机制将有助于开发新的治疗方法。