Src Regulates the Activity of the ING1 Tumor Suppressor

PLoS One. 2013 Apr 9;8(4):e60943. doi: 10.1371/journal.pone.0060943. Print 2013.

Abstract

The INhibitor of Growth 1 (ING1) is stoichiometric member of histone deacetylase (HDAC) complexes and functions as an epigenetic regulator and a type II tumor suppressor. It impacts cell growth, aging, apoptosis, and DNA repair, by affecting chromatin conformation and gene expression. Down regulation and mislocalization of ING1 have been reported in diverse tumor types and Ser/Thr phosphorylation has been implicated in both of these processes. Here we demonstrate that both in vitro and in vivo, the tyrosine kinase Src is able to physically associate with, and phosphorylate ING1, which results in a nuclear to cytoplasmic relocalization of ING1 in cells and a decrease of ING1 stability. Functionally, Src antagonizes the ability of ING1 to induce apoptosis, most likely through relocalization of ING1 and down regulation of ING1 levels. These effects were due to both kinase-dependent and kinase-independent properties of Src, and were most apparent at elevated levels of Src expression. These findings suggest that Src may play a major role in regulating ING1 levels during tumorigenesis in those cancers in which high levels of Src expression or activity are present. These data represent the first report of tyrosine kinase-mediated regulation of ING1 levels and suggest that kinase activation can impact chromatin structure through the ING1 epigenetic regulator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Inhibitor of Growth Protein 1
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Nuclear Proteins / genetics*
  • Phosphorylation
  • Protein Binding
  • Protein Stability
  • Protein Transport
  • Signal Transduction
  • Tumor Suppressor Proteins / genetics*
  • src-Family Kinases / genetics*
  • src-Family Kinases / metabolism

Substances

  • ING1 protein, human
  • Inhibitor of Growth Protein 1
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • src-Family Kinases

Grant support

This work was supported by grants from the Canadian Breast Cancer Foundation (DJF and KR), the Alberta Cancer Foundation (DJF), the Canadian Institutes of Health Research (KR) and Alberta Innovates-Health Solutions (KR). LY was supported by an Alberta Cancer Foundation Postdoctoral Fellowship Award, ST is a recipient of an ACF Studentship, and KR is a Scientist of the Alberta Heritage Foundation for Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.