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Novel targets that are deregulated by loss of PTEN

由于 PTEN 缺失而解除管制的新靶点

基本信息

批准号：
7544507
负责人：
DEBORAH L. JOHNSON
金额：
$ 22.47万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-06 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7544507
关键词：
1-Phosphatidylinositol 3-Kinase Address Affect Antibodies Apoptosis Biological Assay Cell Cycle Cell Nucleus Cells Complex DNA-Directed RNA Polymerase DNA-Protein Interaction Data Dominant-Negative Mutation Electron Transport Complex III Event Exhibits Gap Junctions Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Goals Human Human Cell Line Human Development In Vitro Investigation Lead Malignant Epithelial Cell Malignant Neoplasms Mediating Molecular Mutate Nuclear Oncogene Deregulation PTEN gene Pathway interactions Phosphoric Monoester Hydrolases Phosphotransferases Polymerase Proteins RNA Polymerase III Repression Reverse Transcriptase Polymerase Chain Reaction Ribosomal Protein S6 Kinase Ribosomal RNA Running Signal Pathway Signal Transduction Signaling Molecule Structure Testing Therapeutic Agents Transcription Factor TFIIIB Transcription Initiation Transcription Process Transcriptional Regulation Transfer RNA Tumor Suppressor Proteins U6 small nuclear RNA Untranslated RNA Work cell growth cellular targeting chromatin immunoprecipitation design gene repression human FRAP1 protein in vivo inhibitor/antagonist mutant novel novel therapeutics polypeptide promoter reconstitution response transcription factor transcription factor TFIIIC tumor tumor progression

项目摘要

PTEN is a tumor suppressor and the first phosphatase identified to be frequently mutated/deleted somatically in a variety of human cancers. Substantial evidence supports that loss of PTEN promotes the development of human cancer. PTEN normally serves to repress the activation of the PIS kinase signaling pathway. However, little is yet known regarding PTEN-mediated changes in gene expression that are lost in cells that lack PTEN. Our studies will examine the novel idea that PTEN, and PIS kinase/Akt signaling, regulates RNA polymerase (pol)Ill-dependent gene expression and that this regulatory event is lost in human carcinoma cells that exhibit reduced PTEN expression. As RNA pol III products, tRNAs and 5S rRNAs, determine the translational capacity of cells, repression of RNA pol III transcription by PTEN is likely to be fundamental to its tumor suppressing function. Our studies will identify new targets of PTEN, and elucidate in detail, the mechanism for how loss of PTEN leads to deregulation of RNA pol III transcription in several different human cell lines. By comparing cells that contain alterations in the levels of functional PTEN, we will: (1) Determine whether PTEN represses transcription of the three major classes of RNA pol III promoters; (2) Determine the PTEN/Akt-regulated signaling pathways involved in this response; and determine whether PTEN may also function in the nucleus to directly repress the transcription process. (3) Identify quantitative and/or qualitative changes in factor(s) of the RNA pol III transcription machinery that is/are specifically targeted by PTEN; and (4) Determine how these changes in the transcription components alters their function and the formation of transcription initiation complexes in vivo. From these studies, we will identify novel downstream targets of PTEN that are important for its function as a tumor suppressor and provide the first evidence that the deregulation of RNA pol III genes is a consequence of the loss of PTEN. Defining the PTEN-mediated signaling pathways and targets that are aberrantly regulated in cells that have lost PTEN function, giving rise to these specific consequences gene expression, will provide a valuable nexus for investigation of therapeutic agents that mimic PTEN function.

PTEN是一种肿瘤抑制因子，也是第一个被发现经常发生突变/缺失的磷酸酶