title: Brn-3a/POU4F1 interacts with and differentially affects p73-mediated transcription.
abstract: The Brn-3a/POU4F1 POU transcription factor is critical for the survival and differentiation of specific sensory neurons during development or upon injury; by regulating expression of target genes, either directly or indirectly upon interaction with other proteins. In this study, we demonstrated the physical interaction of Brn-3a with different p73 isoforms and showed co-localization in sensory neurons arising from the neural crest. The biological effects of p73/ Brn-3a interaction depend on the particular p73 isoform, because co-expression of Brn-3a with TAp73 enhanced cell cycle arrest, whereas Brn-3a and DeltaNp73 cooperated to increase protection from apoptosis. Brn-3a antagonized TAp73 transactivation of pro-apoptotic Bax, but co-operated to increase transcription of the cell cycle regulator p21 CIP1/Waf1. The region 425-494 amino acids within the TAp73 C terminus were critical for Brn-3a to repress Bax transactivation, but not for cooperation on the p21 CIP1/Waf1 promoter. Our results suggest that co-factors binding to the p73 C terminus facilitate maximal activation on the Bax but not p21 CIP1/Waf1 promoter and that Brn-3a modulates this interaction. Thus, the physical interaction of Brn-3a with specific p73 isoforms will be critical for determining cell fate during neuronal development or in injured neurons expressing both factors.
authors.affiliation: Medical Molecular Biology Unit, Institute of Child Health, University College London, London, UK.
authors.forename: C D
authors.initials: CD
authors.lastname: Hudson
authors.forename: A E
authors.initials: AE
authors.lastname: Sayan
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.forename: R A
authors.initials: RA
authors.lastname: Knight
authors.forename: D S
authors.initials: DS
authors.lastname: Latchman
authors.forename: V
authors.initials: V
authors.lastname: Budhram-Mahadeo
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009432:Neural Crest / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009475:Neurons, Afferent / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050819:Transcription Factor Brn-3A / Q000378:metabolism*; D050820:Transcription Factor Brn-3B / Q000378:metabolism*; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C000606460:TP73 protein, human; D050819:Transcription Factor Brn-3A; D050820:Transcription Factor Brn-3B; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C000606369:delta Np73 protein, human