雄激素对 TGF-β 信号传导的控制-猫眼课题宝

雄激素对 TGF-β 信号传导的控制

批准号：

7345468

负责人：

DAVID DANIELPOUR

金额：

$29.35万

依托单位：

CASE WESTERN RESERVE UNIVERSITY

依托单位国家：

美国

项目类别：

财政年份：

2004

资助国家：

美国

项目状态：

已结题

起止时间：

2004-03-02 至 2010-02-28

来源：

https://reporter.nih.gov/project-details/7345468

关键词：

Ablation Accounting Adenoviruses Affect Amino Acid Substitution Amino Acids Androgen Receptor Androgens Animals Apoptosis Apoptotic Autocrine Communication Binding Binding Proteins Biological Biological Assay Biology Candidate Disease Gene Cell Adhesion Cell Count Cell Cycle Cell Cycle Arrest Cell Death Cell Line Cell Proliferation Cells Co-Immunoprecipitations Complementary DNA Cyclin A DNA DNA Sequence DU145 Dependence Development Dominant-Negative Mutation Electrophoretic Mobility Shift Assay Elements Epithelial Cells FOS gene Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Growth Immunoglobulin G Immunoprecipitation In Vitro Induction of Apoptosis Inhibition of Apoptosis Intercept Iodine LNCaP Laboratories Length Ligands Light Link Luciferases Malignant - descriptor Malignant neoplasm of prostate Mediator of activation protein Modeling Molecular Profiling Mutagenesis Mutation Northern Blotting Nuclear Receptor Coactivator 4 Numbers Oncogenes Pathway interactions Pattern Peptides Phenotype Play Principal Investigator Propidium Prostate Prostate Adenocarcinoma Prostatic Protein Overexpression Proteins Proteomics Receptor Gene Regulation Regulator Genes Reporter Reporting Research Personnel Resistance Role Signal Pathway Signal Transduction Site-Directed Mutagenesis Small Interfering RNA Staining method Stains Stanolone Steroids Structure System Testing Therapeutic Therapeutic Intervention Thinking Thymidine Tissues Transcriptional Activation Transfection Transforming Growth Factor beta Tumor Suppression Tumor Suppressor Proteins Western Blotting Yeasts annexin A5 anticancer research autocrine base cDNA Expression carcinogenesis cell growth cell type expression vector human RIPK1 protein paracrine peptide analog programs promoter receptor receptor binding receptor expression research study response retroviral transduction success tumorigenic yeast two hybrid system

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DESCRIPTION (provided by applicant): Transforming growth factor-betas (TGF-betas) are 25 kDa multifunctional autocrine/paracrine peptides with potent activity on growth suppression and apoptosis of epithelial cells. In the prostate, expression of TGF-beta protein and their receptors are induced upon androgen ablation, coincident with apoptotic cell death that occurs concomitantly in this tissue. Prostatic cells lose dependence on androgens and become resistant to TGF-beta responses during carcinogenesis, through mechanisms that remain to be defined. Further support for a tumor suppressor role of TGF-beta in the prostate comes from studies where we ablated TGF-beta signaling in two non-tumorigenic cell lines (NRP-152 and DP-153) by retroviral transduction of a dominant-negative TbetaRII, and showed the consequent loss of response to TGF-beta triggers malignant transformation. Loss of TGF-beta receptor expression is one of many potential mechanisms of TGF-beta resistance. Other pathways may involve activation of certain oncogenes that intercept TGF-beta signals at various levels. We have recently reported that DHT can directly block TGF-beta signaling through an association between AR and Smad3, leading to the transcriptional inactivation of Smad3 in LNCaP and NRP-154 prostatic epithelial cells. We provide evidence using EMSAs that AR's inhibitory effect is through blocking the binding of Smad3 to Smad Binding Elements (SBE) of target genes. Here we propose to investigate:1) the effects of DHT/AR on growth arrest and apoptosis induced by TGF-beta (or active Smad3), 2) expression of TGF-beta inducible genes by DHT/AR, 3) the structure/functional basis behind the binding of AR to Smad3, 4) possible function of AR co-activators as co-regulators or Smad3 through AR, and 5) differences in the interaction of AR with Smad3 in various nontumorigenic and tumorigenic cell lines. We believe these studies will most certainly impact on the therapeutic intervention of prostate cancer.

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