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Investigating the Roles and Regulation of FOXO Transcription Factors in GBM and basal breast cancer

研究 FOXO 转录因子在 GBM 和基底乳腺癌中的作用和调节

基本信息

批准号：
10359145
负责人：
Megan E Keniry
金额：
$ 10.9万
依托单位：
UNIVERSITY OF TEXAS RIO GRANDE VALLEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10359145
关键词：
1-Phosphatidylinositol 3-Kinase Address Aging Apoptosis Binding Biological Breast Cancer cell line Bypass CRISPR/Cas technology Cancer Prognosis Cancer cell line Cell Cycle Progression Cell Nucleus Cells Clustered Regularly Interspaced Short Palindromic Repeats Confocal Microscopy Cytosine Data Development Diabetes Mellitus Environment Epigenetic Process FOXO1A gene FOXO3A gene Funding Gene Expression Gene Mutation Genes Genetic Models Genetic Models for Cancer Genetic Transcription Genomic approach Glioblastoma Goals Growth Hispanic Hispanic-serving Institution Histones Human Investigation Lead Lymphoma cell Malignant Neoplasms Maps Mediating Methylation Mission Modeling Modification Molecular Mus Mutate Mutation Nerve Degeneration Nuclear Output Pathway interactions Pharmacology Prognosis Promoter Regions Proteins Proto-Oncogene Proteins c-akt Publishing Quantitative Reverse Transcriptase PCR RNA Interference RNA Polymerase II Regulation Reporting Research Research Personnel Role STAT3 gene Sampling Signal Transduction Students T-Lymphocyte Tail Testing Texas Therapeutic Intervention Tumor Suppressor Proteins United States United States National Institutes of Health Universities Western Blotting Work cancer cell cancer therapy chromatin immunoprecipitation effective therapy efficacious treatment embryonic stem cell genetic manipulation genome editing human disease innovation large cell Diffuse non-Hodgkin&apos s lymphoma malignant breast neoplasm novel overexpression pluripotency programs promoter rational design recruit stem cell genes stem cells therapeutically effective transcription factor translational impact

项目摘要

PROJECT SUMMARY: This proposal examines newly identified cellular roles for FOXO transcription factors in regulating stem cell- related gene expression and signal transduction in cancer. The phosphatidylinositol 3 kinase (PI3K) pathway is almost universally mutated to an activate state in cancer to drive growth and survival. Partially redundant, evolutionarily conserved FOXO -1, -3 and -4 transcription factors are best known for hindering cell cycle progression and inducing apoptosis on the PI3K pathway. Canonically, PI3K indirectly inactivates FOXO factors. However, we found FOXO factors in the nucleus of PI3K-activated cancer cell lines such as U87MGs and BT549s, suggesting novel regulation and roles for these factors in these settings. Other researchers have found FOXO factors in the nucleus in contexts with activated PI3K (embryonic stem cells and DLBCL). To address the role of FOXO factors in PI3K-activated cancers such as U87MG, we utilized an innovative approach (CRISPR, corroborated with RNAi and overexpression studies). Our preliminary evidence indicated that FOXO3 disruption reduced the expression of stem cell-related genes in U87MGs such as OCT4 and SOX2, whereas exogenous FOXO3 induced these genes. Aim 1 will identify mechanisms that promote FOXO nuclear localization in these novel contexts. Aim 2 will define precise molecular mechanisms that are utilized by FOXO factors to induce the expression of stem cell-related genes in PI3K-activated cancers such as U87MG and BT549 cells. These aims will be accomplished by employing qRT-PCR, western blot analyses, chromatin immuno-precipitation analyses, genomics approaches and confocal microscopy. The impact of FOXO factors on stem cell gene expression and signal transduction has broad ramifications to prevalent human diseases such as cancer, neurodegeneration, diabetes and aging. Proposed studies and research enhancement objectives will be conducted at the second largest Hispanic-serving Institution in the United States, the University of Texas Rio Grande Valley (UTRGV), which has not been a major recipient of NIH support. Funding and completion of these studies will increase research capabilities at UTRGV, which serves over 27,000 students who are 89% Hispanic thereby serving the mission of the SCORE Program.

项目总结:

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NVP-BEZ235 or JAKi Treatment leads to decreased survival of examined GBM and BBC cells.

DOI：
10.1016/j.ctarc.2021.100340
发表时间：
2021
期刊：
Cancer treatment and research communications
影响因子：
0
作者：
Vazquez N;Lopez A;Cuello V;Persans M;Schuenzel E;Innis-Whitehouse W;Keniry M
通讯作者：
Keniry M

PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells.