TIF1β is phosphorylated at serine 473 in colorectal tumor cells through p38 mitogen-activated protein kinase as an oxidative defense mechanism

Biochem Biophys Res Commun. 2017 Oct 21;492(3):310-315. doi: 10.1016/j.bbrc.2017.08.117. Epub 2017 Aug 31.

Abstract

TIF1β is a pleiotropic regulator of a diverse range of cellular processes such as DNA repair or gene repression in stem cells. This functional switch depends on phosphorylation at serine residue 473 and multiple pathways exist to accomplish this. However, the effects of exogenous reactive oxygen species (ROS) generated by bacterial flora and dietary metabolites in the colonic lumen or chemotherapy on TIF1β have not been determined. We report here that exposure of colorectal cancer (CRC) cell lines DLD-1 and HCT116 to hydrogen peroxide specifically induces TIF1β Ser473 phosphorylation. Hydrogen peroxide also induces primarily p38 MAPK and some p42/44 MAPK phosphorylation. Chemical inhibition of p38 MAPK and p42/44 MAPK reduced phosphorylation of TIF1β serine 473 and increased CRC cell death upon peroxide exposure. Taken together, this suggests that it is primarily peroxide-induced p38 MAPK that mediates Ser473 phosphorylation and activation of TIF1β to enable more efficient DNA repair to assist in tumor cell survival against exogenous ROS.

Keywords: Chromatin; Colorectal cancer; MAPKs; Oxidative stress; TIF1β phosphorylation.

MeSH terms

  • Cell Death / drug effects
  • Cells, Cultured
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Dose-Response Relationship, Drug
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Oxidative Stress* / drug effects
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism*
  • RNA, Small Interfering / pharmacology
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / chemistry*
  • Repressor Proteins / metabolism*
  • Structure-Activity Relationship
  • Tripartite Motif-Containing Protein 28
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • RNA, Small Interfering
  • Repressor Proteins
  • Phosphoserine
  • Hydrogen Peroxide
  • TRIM28 protein, human
  • Tripartite Motif-Containing Protein 28
  • p38 Mitogen-Activated Protein Kinases