Spatiotemporal switch from DeltaNp73 to TAp73 isoforms during nephrogenesis: impact on differentiation gene expression.
p73 is a member of the p53 gene family, which also includes p53 and p63. These proteins share sequence similarity and target genes but also have divergent roles in cancer and development. Unlike p53, transcription of the p73 gene yields multiple full-length (transactivation (TA) domain) and amino terminus-truncated (DeltaN) isoforms. DeltaNp73 acts in a dominant negative fashion to inhibit the actions of TAp73 and p53 on their target genes, promoting cell survival and proliferation and suppressing apoptosis. The balance between TAp73 and its negative regulator, DeltaNp73, may therefore represent an important determinant of developmental cell fate. There is little if anything known regarding the developmental regulation of the p73 gene. In this study, we showed that TAp73 and DeltaNp73 exhibit reciprocal spatiotemporal expression and functions during nephrogenesis. TAp73 was predominantly expressed in the differentiation domain of the renal cortex in an overlapping manner with the vasopressin-sensitive water channel aquaporin-2 (AQP-2). Chromatin immunoprecipitation assays demonstrated that the endogenous AQP-2 promoter was occupied by TAp73 in a developmentally regulated manner. Furthermore TAp73 stimulated AQP-2 promoter-driven reporter expression. TAp73 also activated the bradykinin B2 receptor (B2R) promoter, a developmentally regulated gene involved in regulation of sodium excretion. The transcriptional effects of TAp73 on AQP-2 and B2R were independent of p53. In marked contrast to TAp73, DeltaNp73 isoforms were induced early in development and were preferentially expressed in proliferating nephron precursors. Moreover DeltaNp73 was a potent repressor of B2R gene transcription. We conclude that the p73 gene is developmentally regulated during kidney organogenesis. The spatiotemporal switch from DeltaNp73 to TAp73 may play an important role in the terminal differentiation program of the developing nephron.
Saifudeen
Zubaida
Z
Department of Pediatrics, Section of Pediatric Nephrology, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Diavolitsis
Virginia
V
Stefkova
Jana
J
Dipp
Susana
S
Fan
Hao
H
El-Dahr
Samir S
SS
D000818:Animals; D000831:Animals, Newborn; D051399:Aquaporin 2; D020346:Aquaporins / Q000737:chemistry / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005091:Exons; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D007150:Immunohistochemistry; D007668:Kidney / Q000254:growth & development* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D043782:Receptor, Bradykinin B2 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D014867:Water / Q000737:chemistry
C496024:Aqp2 protein, mouse; C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D020346:Aquaporins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D043782:Receptor, Bradykinin B2; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D014867:Water