FAM193A is a positive regulator of p53 activity

Maria M Szwarc; Anna L Guarnieri; Molishree Joshi; Huy N Duc; Madison C Laird; Ahwan Pandey; Santosh Khanal; Emily Dohm; Aimee K Bui; Kelly D Sullivan; Matthew D Galbraith; Zdenek Andrysik; Joaquin M Espinosa

doi:10.1016/j.celrep.2023.112230

FAM193A is a positive regulator of p53 activity

Cell Rep. 2023 Mar 28;42(3):112230. doi: 10.1016/j.celrep.2023.112230. Epub 2023 Mar 9.

Authors

Affiliations

¹ Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
² Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
³ Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁴ Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
⁵ Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, Section of Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁶ Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁷ Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: zdenek.andrysik@cuanschutz.edu.
⁸ Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: joaquin.espinosa@cuanschutz.edu.

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.

Keywords: CP: Cancer; CP: Molecular biology; CRISPR; MDM2; MDM4; MDMX; Nutlin; apoptosis; cell-cycle arrest; p53.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Antineoplastic Agents* / pharmacology
Apoptosis
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Humans
Neoplasms* / pathology
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-mdm2 / metabolism
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Antineoplastic Agents
Cell Cycle Proteins
MDM4 protein, human
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-mdm2
Tumor Suppressor Protein p53
FAM193A protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding