FAM193A is a positive regulator of p53 activity
Summary: 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 het...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-03-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723002413 |
| _version_ | 1811155515800027136 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Maria M. Szwarc |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-10T04:35:37Z |
| format | Article |
| id | doaj.art-d6d8dbe69f8949288e595955b15dcfa6 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-10T04:35:37Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-d6d8dbe69f8949288e595955b15dcfa62023-03-10T04:34:52ZengElsevierCell Reports2211-12472023-03-01423112230FAM193A is a positive regulator of p53 activityMaria M. Szwarc0Anna L. Guarnieri1Molishree Joshi2Huy N. Duc3Madison C. Laird4Ahwan Pandey5Santosh Khanal6Emily Dohm7Aimee K. Bui8Kelly D. Sullivan9Matthew D. Galbraith10Zdenek Andrysik11Joaquin M. Espinosa12Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Functional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USAFunctional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USAFunctional Genomics Facility, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Peter MacCallum Cancer Centre, Melbourne, VIC 3000, AustraliaDepartment of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment 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, USADepartment 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, USADepartment 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; Corresponding authorDepartment 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; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723002413CP: Molecular biologyCP: Cancer |
| spellingShingle | 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 FAM193A is a positive regulator of p53 activity Cell Reports CP: Molecular biology CP: Cancer |
| title | FAM193A is a positive regulator of p53 activity |
| title_full | FAM193A is a positive regulator of p53 activity |
| title_fullStr | FAM193A is a positive regulator of p53 activity |
| title_full_unstemmed | FAM193A is a positive regulator of p53 activity |
| title_short | FAM193A is a positive regulator of p53 activity |
| title_sort | fam193a is a positive regulator of p53 activity |
| topic | CP: Molecular biology CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723002413 |
| work_keys_str_mv | AT mariamszwarc fam193aisapositiveregulatorofp53activity AT annalguarnieri fam193aisapositiveregulatorofp53activity AT molishreejoshi fam193aisapositiveregulatorofp53activity AT huynduc fam193aisapositiveregulatorofp53activity AT madisonclaird fam193aisapositiveregulatorofp53activity AT ahwanpandey fam193aisapositiveregulatorofp53activity AT santoshkhanal fam193aisapositiveregulatorofp53activity AT emilydohm fam193aisapositiveregulatorofp53activity AT aimeekbui fam193aisapositiveregulatorofp53activity AT kellydsullivan fam193aisapositiveregulatorofp53activity AT matthewdgalbraith fam193aisapositiveregulatorofp53activity AT zdenekandrysik fam193aisapositiveregulatorofp53activity AT joaquinmespinosa fam193aisapositiveregulatorofp53activity |