title: Regulatory feedback loop between TP73 and TRIM32.
abstract: The p73 transcription factor is one of the members of the p53 family of tumor suppressors with unique biological functions in processes like neurogenesis, embryonic development and differentiation. For this reason, p73 activity is tightly regulated by multiple mechanisms, including transcription and post-translational modifications. Here, we identified a novel regulatory loop between TAp73 and the E3 ubiquitin ligase tripartite motif protein 32 (TRIM32). TRIM32, a new direct p73 transcriptional target in the context of neural progenitor cells, is differentially regulated by p73. Although TAp73 binds to the TRIM32 promoter and activates its expression, TAp73-induced TRIM32 expression is efficiently repressed by DNp73. TRIM32 in turn physically interacts with TAp73 and promotes its ubiquitination and degradation, impairing p73-dependent transcriptional activity. This mutual regulation between p73 and TRIM32 constitutes a novel feedback loop, which might have important implications in central nervous system development as well as relevance in oncogenesis, and thus emerges as a possible therapeutic target.
authors.affiliation: Instituto de Biomedicina (IBIOMED), Department of Molecular Biology, Universidad de León, Campus de Vegazana, León 24071, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Gonzalez-Cano
authors.forename: A-L
authors.initials: AL
authors.lastname: Hillje
authors.forename: S
authors.initials: S
authors.lastname: Fuertes-Alvarez
authors.forename: M M
authors.initials: MM
authors.lastname: Marques
authors.forename: A
authors.initials: A
authors.lastname: Blanch
authors.forename: R W
authors.initials: RW
authors.lastname: Ian
authors.forename: M S
authors.initials: MS
authors.lastname: Irwin
authors.forename: J C
authors.initials: JC
authors.lastname: Schwamborn
authors.forename: M C
authors.initials: MC
authors.lastname: Marín
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C514011:TRIM32 protein, mouse; D044767:Ubiquitin-Protein Ligases