INKA2, a novel p53 target that interacts with the serine/threonine kinase PAK4

Liu,Yu‑Yu; Tanikawa,Chizu; Ueda,Koji; Matsuda,Koichi

doi:10.3892/ijo.2019.4786

INKA2, a novel p53 target that interacts with the serine/threonine kinase PAK4

Authors:
- Yu‑Yu Liu
- Chizu Tanikawa
- Koji Ueda
- Koichi Matsuda
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Affiliations: Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo 108‑8639, Tokyo, Japan, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo 108‑8639, Tokyo, Japan, Project for Realization of Personalized Cancer Medicine, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo 135‑8550, Japan
Published online on: April 15, 2019 https://doi.org/10.3892/ijo.2019.4786
Pages: 1907-1920
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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 damage‑induced mouse and human transcriptome data to identify novel downstream targets of p53. Our method selected genes with an induced expression in multiple organs of X‑ray‑irradiated p53 wild‑type 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 p53‑dependent 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 wild‑type 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/threonine‑protein kinase, p21 (RAC1) activated kinase (PAK)4, which phosphorylates β‑catenin to prevent ubiquitin‑proteasomal degradation. As β‑catenin was downregulated in a stable INKA2‑expressing 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 PAK4‑β‑catenin pathway.

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