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Integrative approaches to elucidate p53 transcriptional networks during carcinogenesis

阐明致癌过程中 p53 转录网络的综合方法

基本信息

批准号：
10806805
负责人：
LAURA D ATTARDI
金额：
$ 12.55万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-14 至 2029-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10806805
关键词：
Adenocarcinoma Cell Affect Affinity Affinity Chromatography Alternative Splicing Alveolar Binding Biological Biological Assay Biological Models CRISPR screen Cancer Etiology Cell Cycle Arrest Cell Differentiation process Cell Line Cell Proliferation Cells Cessation of life Disease Early Diagnosis Early treatment Elements Embryo Evolution Fibroblasts Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Human Individual KRASG12D Knock-in Mouse Lung Adenocarcinoma Malignant Neoplasms Mass Spectrum Analysis Mediating Modeling Molecular Mouse Strains Mus Mutate Mutation Oncogenes Parents Pathway interactions Play Proliferating Property Proteins Proteome Proteomics Puma RNA Splicing RNA-Binding Proteins Research Role Signal Transduction System TP53 gene Testing Therapeutic Transactivation Transcription Coactivator Transcriptional Activation Transcriptional Activation Domain Transplantation Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Variant Zinc Fingers cancer cell cancer therapy carcinogenesis experience experimental study improved in vitro Model in vivo insight knock-down lung injury lung regeneration mouse model mutant novel parent grant posttranscriptional programs protein protein interaction single-cell RNA sequencing small hairpin RNA standard of care targeted treatment therapeutic target tool tumor tumor barcoding and sequencing tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT The TP53 tumor suppressor gene is mutated in over half of all human cancers, but the mechanisms through which p53 suppresses cancer in vivo remain incompletely understood. Notably, there are no standard-of-care cancer therapies based on the p53 pathway. In this proposal, we strive to deconstruct the pathways through which p53 suppresses cancer to illuminate pathways dysregulated upon p53 loss that could ultimately be targeted therapeutically. We previously performed unbiased in vivo shRNA and CRISPR/Cas9 screens for p53 target genes important for tumor suppression and identified Zmat3 as the top hit in both screens. Zmat3 encodes a zinc finger RNA-binding protein that we found acts by modulating alternative splicing, revealing a new branch of p53-mediated tumor suppression. Given the critical role for alternative splicing in cancer, we hypothesize that studying p53 pathways at the post-transcriptional level, such as through splicing and proteomics analyses, will yield novel insights into p53-mediated tumor suppression. In Theme 1, we propose to identify p53-dependent splicing and proteome changes, including both Zmat3-dependent and Zmat3- independent ones, that could explain tumor suppression in mouse LUAD and HCC. We will test the importance of genes found in these analyses for LUAD and HCC suppression using a quantitative in vivo tumor assay known as Tuba-seq. In Theme 2, we will pursue our observation that p53 repurposes a role in lung regeneration, in which it drives alveolar type 1 cell differentiation upon lung injury, to suppress LUAD. Through single cell (sc)RNA-seq and scATAC-seq analyses, we will ask how p53 status dictates the evolutionary path of KrasG12D-expressing alveolar type 2 cells and how p53 transcriptional programs change with cell state across LUAD evolution in mouse models. We will also ask how cells in the tumor microenvironment (TME) affect cancer cell trajectories in wild-type and p53-deficient tumors. To define genes functionally important for cancer cell state transitions and crosstalk between cancer cells and TME components, we will employ scPerturb-seq. In this diversity supplement, Dr. Tambo will perform a new project related to Theme 2 of the R35 to expand our understanding of p53 action in LUAD suppression by using proteomics to identify p53 interacting partners. We will perform tandem affinity tag purification of wild-type p53 and p53 transactivation domain mutants with altered tumor suppression properties to identify those p53-interactors most relevant for tumor suppression. We will then test the roles of these p53-interacting proteins in tumor suppression in a mouse transplant system and we will define the roles of these p53-interactors in p53 target gene regulation and proliferation suppression. Ultimately, we will identify those p53-interacting proteins most relevant for LUAD suppression in the scPerturb-seq experiments in vivo. Collectively, these studies will deconstruct p53-mediated tumor suppression in vivo at an unprecedented molecular depth, which will provide crucial new insight into how to modulate p53 pathways in therapeutic strategies for cancer.

项目总结/文摘

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer.

DOI：
10.1016/j.ccell.2017.09.007
发表时间：
2017-10-09
期刊：
Cancer cell
影响因子：
50.3
作者：
Mello SS;Valente LJ;Raj N;Seoane JA;Flowers BM;McClendon J;Bieging-Rolett KT;Lee J;Ivanochko D;Kozak MM;Chang DT;Longacre TA;Koong AC;Arrowsmith CH;Kim SK;Vogel H;Wood LD;Hruban RH;Curtis C;Attardi LD
通讯作者：
Attardi LD

Deciphering p53 signaling in tumor suppression.

DOI：
10.1016/j.ceb.2017.11.005
发表时间：
2018-04
期刊：
Current opinion in cell biology
影响因子：
7.5
作者：
Mello SS;Attardi LD
通讯作者：
Attardi LD

p53 and Tumor Suppression: It Takes a Network.

DOI：
10.1016/j.tcb.2020.12.011
发表时间：
2021-04
期刊：
Trends in cell biology
影响因子：
19
作者：
Boutelle AM;Attardi LD
通讯作者：
Attardi LD

p19(Arf) is required for the cellular response to chronic DNA damage.

DOI：
10.1038/onc.2015.490
发表时间：
2016-08-18
期刊：
Oncogene
影响因子：
8
作者：
Bieging-Rolett KT;Johnson TM;Brady CA;Beaudry VG;Pathak N;Han S;Attardi LD
通讯作者：
Attardi LD

An anterograde pathway for sensory axon degeneration gated by a cytoplasmic action of the transcriptional regulator P53.

DOI：
10.1016/j.devcel.2021.03.011
发表时间：
2021-04-05
期刊：
Developmental cell
影响因子：
11.8
作者：
Simon DJ;Belsky DM;Bowen ME;Ohn CYJ;O'Rourke MK;Shen R;Kim G;Pitts J;Attardi LD;Tessier-Lavigne M
通讯作者：
Tessier-Lavigne M