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Diverse p63 and p73 isoforms regulate ?133p53 expression through modulation of the internal TP53 promoter activity.

ABSTRACT: In response to stress, p53 binds and transactivates the internal TP53 promoter, thus regulating the expression of its own isoform, ?133p53?. Here, we report that, in addition to p53, at least four p63/p73 isoforms regulate ?133p53 expression at transcriptional level: p63?, ?Np63?, ?Np63? and ?Np73?. 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 ?133p53? expression at both mRNA and protein levels. We also report concomitant variation of p63 and ?133p53 expression during keratinocyte differentiation of HaCat cells and induced pluripotent stem cells derived from mutated p63 ectodermal dysplasia patients. Finally, proliferation assays indicated that ?133p53? isoform regulates the anti-proliferative activities of p63?, ?Np63?, ?Np63? and ?Np73?. Overall, this study shows a strong interplay between p53, p63 and p73 isoforms to orchestrate cell fate outcome.

SUBMITTER: Marcel V

PROVIDER: S-EPMC3321620 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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

Marcel V V Petit I I Murray-Zmijewski F F Goullet de Rugy T T Fernandes K K Meuray V V Diot A A Lane D P DP Aberdam D D Bourdon J-C JC

Cell death and differentiation 20111111 5

In response to stress, p53 binds and transactivates the internal TP53 promoter, thus regulating the expression of its own isoform, Δ133p53α. Here, we report that, in addition to p53, at least four p63/p73 isoforms regulate Δ133p53 expression at transcriptional level: p63β, ΔNp63α, ΔNp63β and ΔNp73γ. 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 i ...[more]

PMID: 22075982

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Project description:The tumor suppressors p53, p73, and p63 are known to function as transcription factors. They promote either growth arrest or apoptosis, depending upon the DNA damage. A number of microRNAs (miRNAs) have been shown to function as transcriptional targets of p53 and they appear to aid p53 in promoting growth arrest and apoptosis. However, the question of p53/p63/p73 regulating the miRNA processing complex has not been addressed in depth so far. Comparative/computational genomic analysis was performed using Target scan, Mami, and Diana software to identify miRNAs that regulate the miRNA processing complex. Here, I present evidence for the first time that the tumor suppressors p53, p63, and p73 function as both positive and negative regulators of the miRNA processing components. Curated p53-dependent miRNA expression data was used to identify p53-miRs that target the components of the miRNA-processing complex. This analysis suggests that most of the components (mRNAs' 3'UTR) of the miRNA processing complex are targeted by p53-miRs. Remarkably, this data revealed the conserved nature of p53-miRs in targeting a number of components of the miRNA processing complex. p53/p73/p63 appears to regulate the major components of the miRNA processing, such as Drosha-DGCR8, Dicer-TRBP2, and Argonaute proteins. In particular, p53/p73/p63 appears to regulate the processing of miRNAs, such as let-7, miR-200c, miR-143, miR-107, miR-16, miR-145, miR-134, miR-449a, miR-503, and miR-21. Interestingly, there seems to be a phenotypic similarity between p63(-/-) and dicer(-/-) mice, suggesting that p63 and dicer could regulate each other. In addition, p63, p73, and the DGCR8 proteins contain a conserved interaction domain. Further, promoters of a number of components of the miRNA processing machinery, including dicer and P2P-R, contain p53-REs, suggesting that they could be direct transcriptional targets of p63/p73/p53. Together, this study provides mechanistic insights into how p53, p63, and p73 regulate the components of the miRNA processing; and how p53, TA-p63, and TA-p73 regulated miRNAs inhibit tumorigenesis, EMT, metastasis, and cancer stem cell proliferation.

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Diverse p63 and p73 isoforms regulate ?133p53 expression through modulation of the internal TP53 promoter activity.

Publications

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

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