Role of AIB1 in YAP/TAZ-TEAD signaling in progression of early stage breast cancer

AIB1 在 YAP/TAZ-TEAD 信号传导中在早期乳腺癌进展中的作用

• 批准号: 9763324
• 负责人: Max Harley Kushner
• 金额: $ 1.79万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-03 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763324
• 关键词: 3-Dimensional; Binding; Bioinformatics; Biological Assay; Cell Extracts; Cells; Chromatin; Co-Immunoprecipitations; Complex; DNA; Data; Disease; Disease Progression; Family; Gene Expression; Genes; Genetic Transcription; Genome; HDAC4 gene; Histones; Hormones; Hyperactive behavior; Incidence; Knock-out; Learning; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Mediating; Methylation; Mutation Analysis; N-terminal; NCOA3 gene; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Normal tissue morphology; Nuclear; Nuclear Receptors; Oncogenes; Oncogenic; Output; Pathway interactions; Pattern; Phenotype; Physiological; Play; Proteins; Reporter; Research; Research Project Grants; Role; Scaffolding Protein; Signal Transduction; Therapeutic Intervention; Tissues; Trans-Activators; Transactivation; Transcription Factor AP-1; Tumor Suppressor Proteins; Xenograft procedure; breast cancer progression; cell growth; chromatin immunoprecipitation; histone modification; in vivo; infiltrating duct carcinoma; inhibitor/antagonist; knock-down; malignant breast neoplasm; member; mouse model; mutant; outcome forecast; overexpression; promoter; protein protein interaction; recruit; scaffold; selective expression; targeted treatment; therapeutic target; transcription factor; transcriptome sequencing; triple-negative invasive breast carcinoma; tumorigenesis

Project Summary/Abstract The nuclear co-activator AIB1 is a member of the NCOA/SRC/p160 family and is known to be amplified and overexpressed breast cancer. AIB1 acts as a scaffolding protein to facilitate assembly of transcription factors, and thereby promotes the transcriptional activity of oncogenic factor such as ER, NFκB, and AP-1. We have previously shown AIB1 co-activation to be directly suppressed by the ANCO1 tumor suppressor, which is lost during breast cancer progression. As a result, AIB1 promotes proliferation and disease progression. Further, in breast cancer mouse models, tissue specific AIB1 knockout reduces disease incidence and delays tumorigenesis. AIB1 contains a N-terminal bHLH/PAS activation domain that reportedly interacts with TEAD, effector of the Hippo pathway. Though the interaction between the AIB1 and TEAD has been shown to be mediated by the bHLH/PAS domain of AIB1, the physiological effects of the protein-protein interaction are unclear. As both proteins are potently oncogenic, their mechanism of interaction in normal tissue, and the extent of the interaction in malignant tissue, may be of extreme consequence and explain the oncogenic role of AIB1. Compared to other transactivators of TEADs, little is known about the specific target gene expression that results from AIB1-TEAD interaction. We hypothesize that the AIB1 binds TEAD near the transactivation domain, cooperates with other co-activators and repressors, and recruits TEAD selectively to promoters of target genes. We aim to define a mechanism of interaction between AIB1 and TEAD (Aim 1A-C), understand perturbations in binding associated with breast cancer progression (Aim 1D), and profile the loci of AIB1-TEAD co-occupancy on the genome (Aim 2). Successful completion of these aims will elucidate the consequences of AIB1-TEAD interaction during breast cancer progression, as well as the loss of ANCO1 suppression.

项目总结/摘要 核共激活因子AIB 1是NCOA/SRC/p160家族的成员，已知其在细胞内扩增， 过度表达的乳腺癌AIB 1作为支架蛋白促进转录因子的组装， 从而促进致癌因子如ER、NFκB和AP-1的转录活性。我们有 先前显示AIB 1共激活被ANCO 1肿瘤抑制因子直接抑制， 在乳腺癌的发展过程中。因此，AIB 1促进增殖和疾病进展。进一步 乳腺癌小鼠模型，组织特异性AIB 1敲除可降低疾病发病率并延迟 肿瘤发生AIB 1含有N-末端bHLH/PAS激活结构域，据报道其与TEAD相互作用， Hippo途径的效应子。虽然AIB 1和TEAD之间的相互作用已被证明是 通过AIB 1的bHLH/PAS结构域介导，蛋白质-蛋白质相互作用的生理效应是 不清楚由于这两种蛋白质都具有潜在的致癌性，因此它们在正常组织中的相互作用机制以及它们之间相互作用的程度， 在恶性组织中的相互作用，可能是极端的后果，并解释AIB 1的致癌作用。 与其他TEAD的反式激活因子相比，人们对TEAD导致的特异性靶基因表达知之甚少。 AIB 1-TEAD相互作用。我们假设AIB 1在反式激活结构域附近结合TEAD， 与其他共激活子和抑制子合作，并选择性地将TEAD募集到靶基因的启动子。 我们的目标是定义AIB 1和TEAD之间的相互作用机制（目标1A-C），了解AIB 1和TEAD之间的干扰。 与乳腺癌进展相关的结合（Aim 1D），并分析AIB 1-TEAD共占据的基因座， 基因组（目标2）。这些目标的成功完成将阐明AIB 1-TEAD的结果 乳腺癌进展过程中的相互作用，以及ANCO 1抑制的丧失。