Regulatory Mechanism of breast cancer growth by Vaccinia-related kinase 2

Abstract

Genetic information is transcribed from genomic DNA to mRNA, which is translated into three dimensional proteins. mRNAs can undergo various post-transcriptional modifications including RNA editing that changes mRNA sequences, which ultimately affects protein function. In this study, RNA editing was found at the 499th base (c.499) of human vaccinia related kinase 2 (VRK2). This RNA editing changes the amino acid of the catalytic domain of VRK2 from isoleucine (with adenine base) to valine (with guanine base). Isoleucine-containing VRK2 has higher kinase activity than valine- containing VRK2, which increases tumor cell proliferation. In previous our study, we found that VRK2 directly interacts with dystrobrevin-binding protein (dysbindin) and results in reducing of its stability. In this study, we showed that isoleucine-containing VRK2 decreases the level of dysbindin than valine- containing VRK2. Dysbindin interacts with cyclin D and regulates the cyclin D expression and function. The decreasing of dysbindin level in isoleucine-containing VRK2 increases the cyclin D than valine form and it leads to increased tumor growth and survival rate reduction. We also showed that, in patient samples, VRK2 level increased in breast cancer tissue compared to normal breast tissue and also increased isoleucine form VRK2 in breast cancer tissue than valine form. In conclusion, we suggest that VRK2, especially dependent on 167th variant amino acid, can be one of the index of tumor progression and proliferation.