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Intrinsic aggregation propensity of the p63 and p73 TI domains correlates with p53R175H interaction and suggests further significance of aggregation events in the p53 family.

ABSTRACT: The high percentage of p53 missense mutations found in cancer has been attributed to mutant acquired oncogenic gain of functions. Different aspects of these tumour-promoting functions are caused by repression of the transcriptional activity of p53 family members p63 and p73. A subset of frequently occurring p53 mutations results in thermodynamic destabilisation of the DNA-binding domain (DBD) rendering this domain highly unstable. These conformational mutants (such as p53R175H) have been suggested to directly bind to p63 and p73 via a co-aggregation mechanism mediated by their DBDs. Although the DBDs of p63 and p73 are in fact not sufficient for the interaction as shown previously, we demonstrate here that the transactivation inhibitory (TI) domains within the ?-isoform-specific C termini of p63 and p73 are essential for binding to p53R175H. Hence, the closed dimeric conformation of inactive TAp63? that renders the TI domain inaccessible prevents efficient interaction. We further show that binding to p53R175H correlates with an intrinsic aggregation propensity of the tetrameric ?-isoforms conferred by an openly accessible TI domain again supporting interaction via a co-aggregation mechanism.

SUBMITTER: Kehrloesser S

PROVIDER: S-EPMC5136486 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Intrinsic aggregation propensity of the p63 and p73 TI domains correlates with p53R175H interaction and suggests further significance of aggregation events in the p53 family.

Kehrloesser Sebastian S Osterburg Christian C Tuppi Marcel M Schäfer Birgit B Vousden Karen Heather KH Dötsch Volker V

Cell death and differentiation 20160722 12

The high percentage of p53 missense mutations found in cancer has been attributed to mutant acquired oncogenic gain of functions. Different aspects of these tumour-promoting functions are caused by repression of the transcriptional activity of p53 family members p63 and p73. A subset of frequently occurring p53 mutations results in thermodynamic destabilisation of the DNA-binding domain (DBD) rendering this domain highly unstable. These conformational mutants (such as p53R175H) have been suggest ...[more]

PMID: 27447112

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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.

Dataset Information

Intrinsic aggregation propensity of the p63 and p73 TI domains correlates with p53R175H interaction and suggests further significance of aggregation events in the p53 family.

Publications

Intrinsic aggregation propensity of the p63 and p73 TI domains correlates with p53R175H interaction and suggests further significance of aggregation events in the p53 family.

Similar Datasets

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