Spatiotemporal Switch from ΔNp73 to TAp73 Isoforms during Nephrogenesis

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 (ΔN) isoforms. ΔNp73 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, ΔNp73, 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 ΔNp73 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, ΔNp73 isoforms were induced early in development and were preferentially expressed in proliferating nephron precursors. Moreover ΔNp73 was a potent repressor of B2R gene transcription. We conclude that the p73 gene is developmentally regulated during kidney organogenesis. The spatiotemporal switch from ΔNp73 to TAp73 may play an important role in the terminal differentiation program of the developing nephron. 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 (ΔN) isoforms. ΔNp73 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, ΔNp73, 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 ΔNp73 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, ΔNp73 isoforms were induced early in development and were preferentially expressed in proliferating nephron precursors. Moreover ΔNp73 was a potent repressor of B2R gene transcription. We conclude that the p73 gene is developmentally regulated during kidney organogenesis. The spatiotemporal switch from ΔNp73 to TAp73 may play an important role in the terminal differentiation program of the developing nephron. Terminal differentiation is a crucial developmental process in which cell cycle arrest is temporally and spatially coordinated with expression of specialized cellular functions. In the kidney, aberrant terminal epithelial cell differentiation leads to renal dysplasia, polycystic kidney disease, and renal cell carcinoma (1Levine E.M. Development. 2004; 131: 2241-2246Crossref PubMed Scopus (19) Google Scholar, 2Li Z.R. Hromchak R. Mudipalli A. Bloch A. Cancer Res. 1998; 58: 4282-4287PubMed Google Scholar, 3Nadasdy T. Lajoie G. Laszik Z. Blick K.E. Molnar-Nadasdy G. Silva F.G. Pediatr. Dev. Pathol. 1998; 1: 49-55Crossref PubMed Scopus (10) Google Scholar). 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Moreover we identified several terminal differentiation genes, including the bradykinin B2 receptor (B2R), 1The abbreviations used are: B2R, B2 receptor; AQP-2, aquaporin-2; RT, reverse transcription; E, embryonic day; PBS, phosphate-buffered saline; ChIP, chromatin immunoprecipitation; CAT, chloramphenicol acetyltransferase; NZ, nephrogenic zone; DZ, differentiation zone; PN, postnatal day; TA, transactivation; ΔN, amino terminus-truncated; E3, ubiquitin-protein isopeptide ligase; MDM-2, murine double minute-2. aquaporin-2 (AQP-2), Na,K-ATPase α1, and angiotensin type 1 receptor (Agtr1), as direct p53 target genes (17Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Investig. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar, 24Saifudeen Z. Marks J. Du H. El-Dahr S.S. Am. J. Physiol. 2002; 283: F727-F733Crossref PubMed Scopus (30) Google Scholar). In keeping with these we that exhibit renal cell cell cycle and expression of nephron differentiation (17Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Investig. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar, 24Saifudeen Z. Marks J. Du H. El-Dahr S.S. Am. J. Physiol. 2002; 283: F727-F733Crossref PubMed Scopus (30) Google Scholar). expression of terminal differentiation genes is but in (17Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Investig. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar), the of regulation by developmentally regulated transcription factors with overlapping functions. studies have identified of p53, and p73 M. V. A. J. Melino G. J. Cell Sci. 2000; 113: PubMed Google and S. M. G. E. S. A. G. PubMed Scopus Google Scholar). genes transcription factors with sequence to p53. in the DNA-binding domain and p73 to and transcription of p53 target genes and to apoptosis the p53 p73 and induced by and in S. A. Cell 1999; PubMed Scopus Google Scholar, Cell 12: Google Scholar, C. P. 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Exp. 2002; PubMed Scopus Google Scholar). the p53 share target genes in during development to The developing kidney is an to terminal differentiation the renal cortex in of cell cycle and differentiation. in the we the the p73 gene in the kidney and the transcriptional of p73 isoforms on the of renal of p73 kidney was from and to the of the was by on a and and of were with for by by 1 of The were to reverse transcription and and in a were in an manner that was by an of to the was with of for for p73 isoforms was on of from a the for of for 1 for 1 and for and for The were on The were as p73 p73 The were on a to the of the isoforms. The of the TAp73 isoforms are: and of expression for TAp73 isoforms. was used as an for The for the were as reverse The is and was for 1 for 1 and for for were from embryonic and in were in and in were by the the as S.S. C.D. W. Int. 1997; Full Text PDF PubMed Scopus Google Scholar). The were p73 was from to amino of the TAp73 isoforms. ΔNp73 was from was a to amino of and these amino with p53 was from amino full-length p53 of with p73 or p63. bradykinin B2R was from to the of AQP-2 was a from M. In negative the was or by the of AQP-2 and TAp73 proteins on the we a double that the of the were to in for with in for the were with the by in with The were with the for and to of the the were in for was by with for that the of the the to and in for the were with and was on from and or with p73 expression as Dipp S. El-Dahr S.S. Am. J. Physiol. Scholar). was to and was as Z. Du H. Dipp S. El-Dahr S.S. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The used in the assays of the in the bradykinin B2R is Z. Du H. Dipp S. El-Dahr S.S. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). full-length p53 or were used in the binding Chromatin was and from the with or were and in a in for for with The was by of was in and with a and the was in DNA was by and in was with to p53 TAp73 or ΔNp73 or were on and of the from the were DNA was proteins were by and used for of the used for of B2R gene as reverse The is of used to the AQP-2 gene promoter as reverse The is Cell and B2R and mouse AQP-2 and the p53 expression have (17Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Investig. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar, Z. Du H. Dipp S. El-Dahr S.S. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). TAp73 and ΔNp73 expression were from G. Melino and M. carcinoma and mouse were in with and in a with were in in in 1 to were with of with or expression of was to for with or was the to the was and cell were a reporter of cell were for for protein or as Z. Du H. Dipp S. El-Dahr S.S. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of TAp73 in the the developing kidney a nephrogenic which proliferating nephron and a differentiation which terminal differentiation to renal In on and the of the We the of TAp73 in the kidney on postnatal and by a which TAp73 this the TAp73 isoforms. a from TAp73 in the In the kidney, TAp73 protein was expressed in the cortex the and nephron and and expressed of TAp73 TAp73 was expressed in the in the DZ, and the from the to was accompanied by a in TAp73 expression and enhanced the of TAp73 expression was in the nephron and in or We the p73 gene is expressed in the kidney and if p73 isoforms in the p73 gene to several which several The by and by the of The and the transcription of TAp73 and the a which is by and and the a amino the in the of the p73 proteins that have p73 proteins to in The also a a domain S. M. G. E. S. A. G. PubMed Scopus Google Scholar, C. P. 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We demonstrated that the mouse and AQP-2 (17Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Investig. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar). AQP-2 is a target of we AQP-2 a kidney with TAp73 and AQP-2 and in and AQP-2 in in and AQP-2 in In of TAp73 were in TAp73 and AQP-2 have overlapping in the We endogenous TAp73 is to the kidney AQP-2 promoter in The that TAp73 and p53 were to the AQP-2 promoter in the kidney the of AQP-2 promoter by p53 and TAp73 was in the kidney, p53 binding to AQP-2 gene TAp73 These were a TAp73 the of the of the or showed the of the between TAp73 and AQP-2 promoter, we assays to the AQP-2 promoter is activated by were with the and expression for p53 or TAp73 isoforms The of p53 and p73 expression were on that p53 is potent in AQP-2 promoter The cell were and for activity. reported (17Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Investig. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar), p53 and activated the AQP-2 promoter to TAp73 also activated the AQP-2 promoter, the by TAp73 isoforms was that induced by p53 In these the developmentally regulated was potent in of AQP-2 that the is in the to the transcription and 17Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Investig. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar). of the AQP-2 promoter was also in that of promoter by TAp73 is we reported the of p53 and B2R in renal epithelial (17Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Investig. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar) and that the B2R promoter a and from the transcription Z. Du H. Dipp S. El-Dahr S.S. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Z. Dipp S. El-Dahr S.S. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). that p53 target genes regulated by TAp73 via direct binding to the E. S. K.H. Sci. U. S. 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The pathways of terminal nephron differentiation We reported that p53 expression in the developing kidney with terminal differentiation and that p53 and the of differentiation genes in the kidney (17Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Investig. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar). that the early steps of nephron induction and on a of aberrant terminal differentiation by expression of proliferation in and expression of renal genes as AQP-2 and B2R (17Saifudeen Z. Dipp S. El-Dahr S.S. J. Clin. Investig. 2002; 109: 1021-1030Crossref PubMed Scopus (43) Google Scholar, 24Saifudeen Z. Marks J. Du H. El-Dahr S.S. Am. J. Physiol. 2002; 283: F727-F733Crossref PubMed Scopus (30) Google Scholar). The demonstrated that TAp73 expression was induced in renal epithelial but was from the nephrogenic Furthermore TAp73 was of the of renal genes, B2R and AQP-2, of p53. as by the TAp73 and p53 were to the AQP-2 promoter in that the regulation is The between p53 and TAp73 that these proteins may or for during kidney development. TAp73 expression is that the ability of TAp73 to for p53 in the kidney is on the of nephron is that was potent in of the AQP-2 promoter, was in B2R of TAp73 isoforms of transcriptional M. S. T. J. PubMed Scopus Google Scholar), is that the TAp73 isoforms have in the development of mouse TAp73 or ΔNp73 isoforms a to the developmental and functions of The for and promoter of the p73 gene during renal organogenesis. 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We R. and D. for the mouse AQP-2 G. Melino and M. for the p73 expression and M. for the AQP-2