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The Translational Regulation of Pro-apoptotic Genes

促凋亡基因的翻译调控

基本信息

批准号：
10737775
负责人：
Wayne Miles
金额：
$ 8.43万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-14 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737775
关键词：
Affect Alleles Apoptosis Apoptotic Auxins BRAT gene Binding Binding Proteins Cancer Cell Growth Cancer Model Cell Cycle Cell Death Cell Proliferation Cells Complex Coupling Data Development E2F transcription factors Gene Expression Regulation Genes Genetic Transcription Genetically Engineered Mouse Genomics Homologous Protein Human Human Engineering Human Genome Individual Kinetics Link LoxP-flanked allele Malignant Neoplasms Mediating Messenger RNA Metabolic Methods MicroRNAs Modeling Mus Necrosis Neoplasm Metastasis Neoplasms Pathologic Pathway interactions Patients Pattern Play Process Production Proliferating Protein Biosynthesis Protein Deficiency Protein Family Proteins RB1 gene RNA RNA Stability RNA analysis RNA-Binding Proteins Regulation Ribosomes Role Survival Rate System Testing Transcript Transcription Coactivator Translation Initiation Translational Regulation Translations Tumor Promotion Tumor Suppressor Proteins Work Zinc Fingers cancer cell cancer therapy cell growth cell growth regulation cytotoxic gene repression human disease human model inducible Cre lung cancer cell member mutant novel posttranscriptional prevent protein complex protein degradation protein function response small cell lung carcinoma therapy design tumor tumorigenesis uncontrolled cell growth

项目摘要

THE TRANSLATIONAL REGULATION OF PRO-APOPTOTIC GENES PROJECT SUMMARY Inactivation of the Retinoblastoma 1 protein (pRB) is one of the most common alterations in cancer. This is because pRB inhibits the activity of three E2F transcription factors, E2F1-3, that control the expression of numerous critical RB-E2F target genes that are required for cancer cell growth, including cell cycle and metabolic factors. In addition to tumor-promoting processes, E2F1-3 also regulates the transcription of tumor-inhibiting genes that play a central role in apoptosis and necrosis. This regulatory circuit links the expression of RB-E2F proliferation and cell death genes, ultimately preventing uncontrolled cell growth. The widespread loss of pRB in cancer underscores a significant puzzle in the field: why don’t pRB-deficient cells simply die? To understand the regulation of the RB-E2F target genes, we profiled RNA and protein changes following pRB- depletion and found that the pro-apoptotic genes were transcribed, but they were not translated into protein. A search for RNA-binding proteins (RBPs) that bound to and blocked the ribosome occupancy of these genes identified the Pumilio complex as direct translational regulators of RB-E2F pro-apoptotic mRNAs. Furthermore, co-deletion of the two core components of the Pumilio complex, PUM1 and PUM2, provoked the cell death of RB1-/- cancer cells via the translation of pro-apoptotic mRNAs. The human Pumilio complex is comprised of PUM and NANOS (NOS) proteins, however significant functional redundancy between the members of the PUM and NOS protein families has limited cellular and tumor studies of the Pumilio complex. To circumvent this issue, we have engineered human cells to express only a single PUM or NOS protein that we can specifically degrade utilizing a novel Auxin-inducible degron system. This technical advance has enabled us to conduct kinetic analysis of RNA stability, localization and translation initiation in the absence of PUM or NOS and to probe the role(s) of different Pumilio complexes in cellular regulation and tumorigenesis. In this new application we propose to: 1) Determine the mechanism(s) of Pumilio complex translational suppression of RB-E2F target pro-apoptotic genes, 2) Define the mechanism of Pumilio complex regulation in RB1 mutant Small Cell Lung Cancer (SCLC) cells, and 3) Determine the role of the Pumilio complex in the Rb1-/-; Trp53-/- mouse SCLC tumorigenesis model. These studies will identify the mechanism(s) that prevent the production of cell death components in highly aggressive and metastatic SCLC.

促凋亡基因的翻译调控

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Thermostability, Tunability, and Tenacity of RNA as Rubbery Anionic Polymeric Materials in Nanotechnology and Nanomedicine-Specific Cancer Targeting with Undetectable Toxicity.

DOI：
10.1021/acs.chemrev.1c00009
发表时间：
2021-07-14
期刊：
Chemical reviews
影响因子：
62.1
作者：
Binzel DW;Li X;Burns N;Khan E;Lee WJ;Chen LC;Ellipilli S;Miles W;Ho YS;Guo P
通讯作者：
Guo P

cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment.

DOI：
10.1186/s13046-021-02221-0
发表时间：
2022-02-08
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
0
作者：
Mishra S;Charan M;Shukla RK;Agarwal P;Misri S;Verma AK;Ahirwar DK;Siddiqui J;Kaul K;Sahu N;Vyas K;Garg AA;Khan A;Miles WO;Song JW;Bhutani N;Ganju RK
通讯作者：
Ganju RK

Clinical Utility of CDK4/6 Inhibitors in Sarcoma: Successes and Future Challenges.