Role for Transcription Factor TFII-I in the Suppression of SSeCKS/Gravin/Akap12 Transcription by Src

Int J Cancer. 2011 Apr 15;128(8):1836-42. doi: 10.1002/ijc.25524.

Abstract

The SSeCKS/Gravin/AKAP12 gene, encoding a kinase scaffolding protein with metastasis-suppressing activity, is transcriptionally downregulated in Src-transformed cells through the recruitment of HDAC1 to a Src-responsive proximal promoter site charged with Sp1, Sp3 and USF1. However, the ectopic expression of these proteins formed a suppressive complex in Src-transformed but not in parental NIH3T3 cells, suggesting the involvement of additional repressor factors. Transcription factor II-I (TFII-I) [general transcription factor 2i (Gtf2i)] was identified by mass spectrometry as being associated with the SSeCKS promoter complex in NIH3T3/Src cells, and moreover, the Src-induced tyrosine phosphorylation of TFII-I significantly increased its binding to the SSeCKS proximal promoter. siRNA-mediated knockdown of TFII-I or the expression of TFII-I(Y248/249F) caused the derepression of SSeCKS in NIH3T3/Src cells. Taken with previous data showing that the tyrosine phosphorylation of TFII-I facilitates its nuclear translocation, these data suggest that Src-family kinase-mediated phosphorylation converts a portion of TFII-I into a transcriptional repressor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A Kinase Anchor Proteins / genetics*
  • A Kinase Anchor Proteins / metabolism
  • Animals
  • Blotting, Western
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Chromatin Immunoprecipitation
  • Chromatography, Liquid
  • Down-Regulation
  • Gene Expression Regulation*
  • Immunoprecipitation
  • Mice
  • NIH 3T3 Cells
  • Phosphorylation
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Transcription Factors, TFII / physiology*
  • Transcription, Genetic
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism*

Substances

  • A Kinase Anchor Proteins
  • Akap12 protein, mouse
  • Cell Cycle Proteins
  • Gtf2i protein, mouse
  • RNA, Messenger
  • Transcription Factors, TFII
  • src-Family Kinases