INKA2, a novel p53 target that interacts with the serine/threonine kinase PAK4.
Int J Oncol
; 54(6): 1907-1920, 2019 Jun.
Article
em En
| MEDLINE
| ID: mdl-31081062
ABSTRACT
The p53 protein is a tumour suppressor and transcription factor that regulates the expression of target genes involved in numerous stress responses systems. In this study, we designed a screening strategy using DNA damageinduced mouse and human transcriptome data to identify novel downstream targets of p53. Our method selected genes with an induced expression in multiple organs of Xrayirradiated p53 wildtype mice. The expression of inka box actin regulator 2 gene, known as Inka2, was upregulated in 12 organs when p53 expression was induced. Similarly, INKA2 was induced in a p53dependent manner at both the mRNA and protein level in human cells treated with adriamycin. Reporter assays confirmed that p53 directly regulated INKA2 through an intronic binding site. The overexpression of INKA2 produced a slight decrease in cancer cell growth in the colony formation assay. Moreover, the analysis of The Cancer Genome Atlas (TCGA) data revealed a decreased INKA2 expression in tumour samples carrying p53 mutations compared with p53 wildtype samples. In addition, significantly higher levels of DNA methylation were observed in the INKA2 promoter in tumour samples, concordant with the reduced INKA2 expression in tumour tissues. These results demonstrate the potential of INKA2 as a cancer cell growth inhibitor. Furthermore, INKA2 protein interacts with the serine/threonineprotein kinase, p21 (RAC1) activated kinase (PAK)4, which phosphorylates ßcatenin to prevent ubiquitinproteasomal degradation. As ßcatenin was downregulated in a stable INKA2expressing cell line, the findings of this study suggest that INKA2 is a novel, direct downstream target of p53 that potentially decreases cell growth by inhibiting the PAK4ßcatenin pathway.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Supressora de Tumor p53
/
Perfilação da Expressão Gênica
/
Peptídeos e Proteínas de Sinalização Intracelular
/
Quinases Ativadas por p21
/
Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Int J Oncol
Ano de publicação:
2019
Tipo de documento:
Article