SAFB 在乳腺癌中的 ER 共抑制功能-猫眼课题宝

SAFB 在乳腺癌中的 ER 共抑制功能

批准号：

8311847

负责人：

Steffi Oesterreich

金额：

$29.39万

依托单位：

UNIVERSITY OF PITTSBURGH AT PITTSBURGH

依托单位国家：

美国

项目类别：

财政年份：

2002

资助国家：

美国

项目状态：

已结题

起止时间：

2002-08-01 至 2014-08-31

来源：

https://reporter.nih.gov/project-details/8311847

关键词：

Affect Apoptosis Area Binding Biology Boxing Breast Cancer Cell Candidate Disease Gene Cell physiology Chromatin Complex DNA Binding Deacetylase Defect Dependency Development Distal Dominant-Negative Mutation Down-Regulation Enhancers Estrogen Receptor alpha Estrogen Receptors Estrogens Funding Gene Expression Gene Targeting Genes HDAC7 histone deacetylase Hormones Knockout Mice Ligands Loss of Heterozygosity Mediating Microarray Analysis Modification Mus Names Neonatal Phosphorylation Play Post-Translational Protein Processing Process Proteins RNA Polymerase II RNA Processing Repression Reproductive system Role SAFB gene Signal Transduction Small Interfering RNA Structure Testing Transcription Coactivator Transcription Repressor/Corepressor Work base biological adaptation to stress cofactor gene repression insight malignant breast neoplasm mutant novel overexpression paralogous gene prenatal promoter protein protein interaction research study response

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We originally cloned SAFB1 as a transcriptional repressor, and it has since been implicated in a number of cellular processes including stress response, apoptosis, RNA processing, hormone response, immortalization, and transformation. During the last funding period we performed detailed structure function studies which identified a transcriptional repression domain, we found that sumoylation of SAFB1 was necessary for its co-repressor activity, and finally, we generated and characterized SAFB1-null mice which showed prenatal and neonatal lethality with surviving mice showing dramatic defects in the development and function of the reproductive system. To gain more insight into SAFB1's role in ERalpha action, we performed an unbiased screen using SAFB1 siRNA knockdown followed by microarray analysis. This experiment revealed a significant role for SAFB1 in estrogen-mediated repression of gene expression, and candidate genes that require SAFB1 for estrogen-mediated downregulation were identified. Here we propose to study how SAFB1 mediates estrogen repression of gene expression. Specifically, we will i) determine how SAFB1 SAFB1 mediates transcriptional repression of estrogen-responsive target genes, ii) characterize HDAC7 as a critical player in SAFB1-mediated repression of estrogen regulated genes, and iii) determine how posttranslational modification by sumoylation affects SAFB1's co-repressor function. This work is highly significant since it provides studies of fundamental mechanisms which may contribute to a change in paradigm of ERalpha's action. While ERalpha has mainly been studied as a transcriptional activator, the study of estrogen- mediated repression of gene expression, and in particular the role of co-repressors, is an understudied area. 1

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