FAM193A is a positive regulator of p53 activity
- Author(s)
- Szwarc, MM; Guarnieri, AL; Joshi, M; Duc, HN; Laird, MC; Pandey, A; Khanal, S; Dohm, E; Bui, AK; Sullivan, KD; Galbraith, MD; Andrysik, Z; Espinosa, JM;
- Details
- Publication Year 2023-03-28,Volume 42,Issue #3,Page 112230
- Journal Title
- Cell Reports
- Publication Type
- Research article
- Abstract
- Inactivation of the p53 tumor suppressor, either by mutations or through hyperactivation of repressors such as MDM2 and MDM4, is a hallmark of cancer. Although many inhibitors of the p53-MDM2/4 interaction have been developed, such as Nutlin, their therapeutic value is limited by highly heterogeneous cellular responses. We report here a multi-omics investigation of the cellular response to MDM2/4 inhibitors, leading to identification of FAM193A as a widespread regulator of p53 function. CRISPR screening identified FAM193A as necessary for the response to Nutlin. FAM193A expression correlates with Nutlin sensitivity across hundreds of cell lines. Furthermore, genetic codependency data highlight FAM193A as a component of the p53 pathway across diverse tumor types. Mechanistically, FAM193A interacts with MDM4, and FAM193A depletion stabilizes MDM4 and inhibits the p53 transcriptional program. Last, FAM193A expression is associated with better prognosis in multiple malignancies. Altogether, these results identify FAM193A as a positive regulator of p53.
- Publisher
- Cell Press
- Keywords
- Humans; *Antineoplastic Agents/pharmacology; Apoptosis; Cell Cycle Proteins/metabolism; Cell Line, Tumor; *Neoplasms/pathology; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-mdm2/metabolism; Tumor Suppressor Protein p53/genetics/metabolism; CP: Cancer; CP: Molecular biology; Crispr; Mdm2; Mdm4; Mdmx; Nutlin; cell-cycle arrest; p53
- Department(s)
- Laboratory Research
- PubMed ID
- 36897777
- Publisher's Version
- https://doi.org/10.1016/j.celrep.2023.112230
- Open Access at Publisher's Site
https://doi.org/10.1016/j.celrep.2023.112230- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-07-11 06:23:37
Last Modified: 2023-07-11 06:25:37