Diverse p63 and p73 isoforms regulate Δ133p53 expression through modulation of the internal TP53 promoter activity

• Published in: Cell death and differentiation Vol. 19; no. 5; pp. 816 - 826
• Main Authors: Marcel, V, Petit, I, Murray-Zmijewski, F, Goullet de Rugy, T, Fernandes, K, Meuray, V, Diot, A, Lane, D P, Aberdam, D, Bourdon, J-C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2012; Nature Publishing Group
• Subjects: Apoptosis; Biochemistry; Biomedical and Life Sciences; Blotting, Western; Cell Biology; Cell Cycle Analysis; Cell Line; Cell Line, Tumor; Cell Proliferation; Chromatin Immunoprecipitation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Humans; Life Sciences; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original Paper; Promoter Regions, Genetic - genetics; Protein Isoforms - genetics; Protein Isoforms - metabolism; Real-Time Polymerase Chain Reaction; Stem Cells; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Protein p73; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Δ133p53; isoforms; promoter activity; p63; p73; p53
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2011.152

In response to stress, p53 binds and transactivates the internal TP53 promoter, thus regulating the expression of its own isoform, Δ133p53 α . Here, we report that, in addition to p53, at least four p63/p73 isoforms regulate Δ133p53 expression at transcriptional level: p63 β , ΔNp63 α , ΔNp63 β and ΔNp73 γ . This regulation occurs through direct DNA-binding to the internal TP53 promoter as demonstrated by chromatin immunoprecipitation and the use of DNA-binding mutant p63. The promoter regions involved in the p63/p73-mediated transactivation were identified using deleted, mutant and polymorphic luciferase reporter constructs. In addition, we observed that transient expression of p53 family members modulates endogenous Δ133p53 α expression at both mRNA and protein levels. We also report concomitant variation of p63 and Δ133p53 expression during keratinocyte differentiation of HaCat cells and induced pluripotent stem cells derived from mutated p63 ectodermal dysplasia patients. Finally, proliferation assays indicated that Δ133p53 α isoform regulates the anti-proliferative activities of p63 β , ΔNp63 α , ΔNp63 β and ΔNp73 γ . Overall, this study shows a strong interplay between p53, p63 and p73 isoforms to orchestrate cell fate outcome.