The involvement of the p53 family member p63 in tumour suppression and in promoting tumorigenesis has been a matter of debate, and a new paper in Nature now clarifies the tumour suppressor function of p63.
The full-length isoform of p63 that contains the transactivation (TA) domain, TAp63, is thought to be a tumour suppressor; so Su, Chakravarti and colleagues investigated this further with cohorts of knockout mice. Aged TAp63+/− and TAp63−/− mice spontaneously developed metastatic sarcomas and carcinomas and had a shorter lifespan than wild-type mice. More of the TAp63+/− mice developed tumours than the TAp63−/− mice, and tumours from the heterozygous mice still had the wild-type gene, which suggested that TAp63 is a haploinsufficient tumour suppressor. They also found that more sarcomas were metastatic in the TAp63+/− mice than in the TAp63−/− mice, whereas the number of metastatic carcinomas was the same in both mice. To further investigate the haploinsufficiency of TAp63, the authors examined the interaction between p53 and TAp63. TAp63 heterozygosity increased the number of metastatic and invasive sarcomas in Trp53+/− mice compared with TAp63−/−;Trp53+/− mice, whereas carcinomas from TAp63−/−;Trp53+/− mice were more metastatic than carcinomas from TAp63+/−;Trp53+/− mice. The authors also observed markers of senescence in osteosarcomas and rhabdomyosarcomas from TAp63−/−;Trp53+/− mice, but not in the same tumour types from TAp63+/−;Trp53+/− mice, suggesting that the induction of senescence as a result of TAp63 homozygous ablation could account for the more severe phenotype of TAp63 heterozygosity. Furthermore, senescence markers were not observed in carcinomas from TAp63−/−;Trp53+/− mice, and these mice had increased polyploidy and chromosome aberrations, which indicated a tissue-specific response to loss of TAp63.
Interestingly, the authors found that dicer expression was reduced in tumours from TAp63−/− mice, and chromatin immunoprecipitation experiments revealed that all isoforms of TAp63 — but not p53 — bind the Dicer1 promoter and activate its transcription. Moreover, re-expression of Dicer1 in TAp63−/− mouse embryonic fibroblasts (MEFs) prevented the ability of these cells to invade, and Dicer1 knockdown in wild-type MEFs increased their invasiveness in vitro, suggesting that reduced levels of dicer increase cell invasion. The authors also found that microRNAs that have been associated with metastasis and are processed by dicer were not processed correctly in TAp63−/− MEFs and that re-expression of TAp63 rescued this. TAp63 also transactivates mir-130b,and further investigation showed that regulation of Dicer1 and mir-130b by TAp63 is important for suppressing metastasis.
These data reveal that TAp63 is a haploinsufficient tumour suppressor with context-specific roles in the suppression of metastasis.
ORIGINAL RESEARCH PAPER
Su, X. et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 467, 986–990 (2010)
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Alderton, G. The burning issue of p63. Nat Rev Cancer 10, 815 (2010). https://doi.org/10.1038/nrc2978