Project 3: Dissecting p53 Action in a Mouse Lymphoma Model Scott Lowe, Ph.D. p53 is a potent tumor suppressor that limits cancer development and contributes to the anti-tumor effects of certain cytotoxic agents. Accordingly, p53 mutations are associated with aggressive cancers, poor patient prognosis and, in some cases, therapy resistance. Our project studies the p53 network using the Ep-myc transgenic mouse, a well characterized model of B cell lymphoma in which p53 profoundly impacts tumorigenesis and treatment outcome. We previously used the E?mu?-myc system to study how p53 loss promotes tumor development and drug resistance, and to explore the relationship between cancer genotype, tumor progression, tumor maintenance, and treatment sensitivity. These studies produced new insights into p53 regulation and effector mechanisms in diverse contexts where it limits proliferation. They also established that p53 loss is required for tumor maintenance and that translational control of cell survival is a druggable mediator of oncogenesis. To facilitate our goals, we developed methods to genetically manipulate E?mu?-myc lymphomas, enabling the rapid and cost-effective production of mice harboring tumors with diverse genotypes. We also incorporated small animal imaging methods to track lymphoma progression and response, and stable and inducible RNAi technology to fine tune and study loss of function phenotypes. Moving forward, we seek to further explore the interplay between cancer genetics and cancer therapy in the E?mu?-myc system in order to produce a more complete picture of the p53 network and its action in vivo. We also wish to understand in detail how p53 mutations impact tumor behavior, and identify new therapeutic targets based on the vulnerabilities they create. We will perform focused RNAi screens to identify new modulators of p53 action relevant to suppressing tumorigenesis and/or modulating therapy response, test the hypothesis that the deletions on chromosome 17p influence cancer biology beyond simply inactivating p53, and identify and characterize drug targets that interact with the p53 tumor suppressor network. Our approach uses genomic data from human lymphoma to inform function studies in mice, and implements a suite of new animal modeling and genetic tools that are time and cost effective.
Successful completion of these studies will functionalize genetic changes that occur in human lymphoma and determine how they impact p53 action and/or influence disease behavior. They may also identify new therapeutic targets for treating p53 mutant cancers, which are often aggressive and more refractory to conventional therapies.
|Rokudai, Susumu; Li, Yingchun; Otaka, Yukihiro et al. (2018) STXBP4 regulates APC/C-mediated p63 turnover and drives squamous cell carcinogenesis. Proc Natl Acad Sci U S A 115:E4806-E4814|
|Rastogi, Chaitanya; Rube, H Tomas; Kribelbauer, Judith F et al. (2018) Accurate and sensitive quantification of protein-DNA binding affinity. Proc Natl Acad Sci U S A 115:E3692-E3701|
|Baugh, Evan H; Ke, Hua; Levine, Arnold J et al. (2018) Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ 25:154-160|
|Agmon, Eran; Solon, Jérôme; Bassereau, Patricia et al. (2018) Modeling the effects of lipid peroxidation during ferroptosis on membrane properties. Sci Rep 8:5155|
|Yozwiak, Carrie E; Hirschhorn, Tal; Stockwell, Brent R (2018) Toward a Microparticle-Based System for Pooled Assays of Small Molecules in Cellular Contexts. ACS Chem Biol 13:761-771|
|Hirschhorn, Tal; Stockwell, Brent R (2018) The development of the concept of ferroptosis. Free Radic Biol Med :|
|Liu, Hengrui; Schreiber, Stuart L; Stockwell, Brent R (2018) Targeting Dependency on the GPX4 Lipid Peroxide Repair Pathway for Cancer Therapy. Biochemistry 57:2059-2060|
|Conrad, Marcus; Kagan, Valerian E; Bayir, Hülya et al. (2018) Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev 32:602-619|
|Zhang, Yan; Larraufie, Marie-Hélène; Musavi, Leila et al. (2018) Design of Small Molecules That Compete with Nucleotide Binding to an Engineered Oncogenic KRAS Allele. Biochemistry 57:1380-1389|
|Shimada, Kenichi; Reznik, Eduard; Stokes, Michael E et al. (2018) Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells. Cell Chem Biol 25:585-594.e7|
Showing the most recent 10 out of 159 publications