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PTEN Tumor Suppressor and Signal Transduction

PTEN 肿瘤抑制因子和信号转导

基本信息

批准号：
9087125
负责人：
Ramon E Parsons
金额：
$ 25.4万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087125
关键词：
Ablation Acetylation Address Apoptosis Binding Binding Sites Biochemistry Breast Cancer Cell Breast Cancer cell line Cancer Prognosis Cell Cycle Arrest Cell Differentiation process Cell Survival Cells Cellular biology Chromatin Chromatin Structure Cytoplasm DNA Binding Domain DNA Modification Process Development E4BP4 Elements Epigenetic Process Equilibrium FOXO1A gene FOXO3A gene Feedback Gene Chips Gene Expression Gene Silencing Gene Targeting Genes Genetic Goals HDAC2 gene Histone Acetylation Histone H3 Histone H4 Histones Human In Vitro Luciferases MLLT7 gene Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Measures Mediating Messenger RNA Methylation Modeling Mus Mutate Mutation Nuclear Oncogenic PTEN gene Pathway interactions Phenotype Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Process Property Proteins Proto-Oncogene Proteins c-akt Recruitment Activity Regulation Reporter Research Role Second Messenger Systems Signal Transduction Stem cells TNFSF10 gene Testing Transcription Repressor/Corepressor Tumor Suppressor Proteins Work base cancer cell cancer stem cell cancer therapy cell behavior chromatin immunoprecipitation chromatin modification epigenetic regulation histone deacetylase 2 histone modification inhibitor/antagonist kinase inhibitor malignant breast neoplasm mutant neoplastic cell outcome forecast overexpression promoter research study second messenger small hairpin RNA stem cell biology theories tissue culture transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): PTEN is a tumor suppressor that is deregulated in a large number of human cancers to activate the oncogenic phosphoinositide-3 kinase (PI3K) pathway. Inactivation of PTEN leads to multiple phenotypes including cancer, changes in stem cell biology and alteration of fundamental processes such as proliferation and apoptosis. We have recently determined that the PI3K pathway activates the transcriptional repressor NFIL3/E4BP4. NFIL3 is over expressed in human breast cancers lacking PTEN. Moreover, over expression of NFIL3 is seen in multiple types of poor-prognosis cancer. We have shown that NFIL3 binds and recruits HDAC2 to promoters to deacetylate histones and silence genes and even represses a recently recognized pool of nuclear FOXO proteins at multiple FOXO target genes. Our findings have broad implications that suggest that NFIL3, which represses numerous non-FOXO targets, could mediate reprogramming of chromatin as a consequence of PTEN mutation. This application will use a combination of biochemistry, signal transduction, mouse genetics, and cancer cell biology to address the following goals 1) to understand the mechanism by which NFIL3 alters the epigenetic regulation of target genes, 2) to determine the contribution of NFIL3 to changes in gene expression and chromatin modification caused by genetic ablation of PTEN, 3) to demonstrate the contribution of NFIL3 to tumor and other phenotypes due to PTEN mutation in mice and cells, and 4) to define how NFIL3 is regulated by PTEN and its implication for PI3K- based cancer therapy.

描述(申请人提供)：PTEN是一种肿瘤抑制因子，在大量人类癌症中被解除调控，激活致癌的磷脂酰肌醇-3激酶(PI3K)途径。PTEN的失活会导致多种表型，包括癌症、干细胞生物学的改变以及增殖和凋亡等基本过程的改变。我们最近确定，PI3K途径激活了转录抑制因子NFIL3/E4BP4。NFIL3在PTEN缺失的乳腺癌中高表达。此外，NFIL3的过度表达可见于多种预后不良的癌症。我们已经证明，NFIL3结合并招募HDAC2到启动子上，以去乙酰化组蛋白和沉默基因，甚至在多个FOXO靶基因上抑制最近发现的核FOXO蛋白池。我们的发现具有广泛的意义，表明抑制许多非FOXO靶标的NFIL3可能介导了PTEN突变导致的染色质重编程。本应用将结合生物化学、信号转导、小鼠遗传学和癌细胞生物学来解决下列目标：1)了解NFIL3改变靶基因表观遗传调控的机制；2)确定NFIL3对PTEN基因突变引起的基因表达和染色质修饰的影响；3)证明NFIL3对小鼠和细胞中PTEN突变引起的肿瘤和其他表型的贡献；以及4)确定PTEN如何调控NFIL3及其对基于PI3K的癌症治疗的意义。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PTEN function: the long and the short of it.

DOI：
10.1016/j.tibs.2014.02.006
发表时间：
2014-04
期刊：
Trends in biochemical sciences
影响因子：
13.8
作者：
Hopkins BD;Hodakoski C;Barrows D;Mense SM;Parsons RE
通讯作者：
Parsons RE

New Frontiers for the NFIL3 bZIP Transcription Factor in Cancer, Metabolism and Beyond.

NFIL3 BZIP转录因子癌症，代谢及其他地区的新领域。

DOI：
10.15190/d.2014.7
发表时间：
2014-04
期刊：
Discoveries (Craiova, Romania)
影响因子：
0
作者：
Keniry M;Dearth RK;Persans M;Parsons R
通讯作者：
Parsons R

Reduction of Pten dose leads to neoplastic development in multiple organs of Pten (shRNA) mice.

DOI：
10.4161/cbt.10.11.13814
发表时间：
2010-12-01
期刊：
Cancer biology & therapy
影响因子：
3.6
作者：
Shen-Li H;Koujak S;Szablocs M;Parsons R
通讯作者：
Parsons R

Molecular pathways: intercellular PTEN and the potential of PTEN restoration therapy.

DOI：
10.1158/1078-0432.ccr-13-2661
发表时间：
2014-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Hopkins BD;Parsons RE
通讯作者：
Parsons RE

Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy.

DOI：
10.1016/j.ccell.2015.05.006
发表时间：
2015-06-08
期刊：
Cancer cell
影响因子：
50.3
作者：
Stratikopoulos EE;Dendy M;Szabolcs M;Khaykin AJ;Lefebvre C;Zhou MM;Parsons R
通讯作者：
Parsons R