TOX3 Is a Neuronal Survival Factor That Induces Transcription Depending on the Presence of CITED1 or Phosphorylated CREB in the Transcriptionally Active Complex

J Cell Sci. 2011 Jan 15;124(Pt 2):252-60. doi: 10.1242/jcs.068759. Epub 2010 Dec 15.

Abstract

TOX3 is a nuclear protein containing a high mobility group (HMG)-box domain, which regulates Ca(2+)-dependent transcription in neurons through interaction with the cAMP-response-element-binding protein (CREB). TOX3 appears to be associated with breast cancer susceptibility and was previously shown to be expressed downstream of a cytoprotective cascade together with CITED1, a transcriptional regulator that does not bind directly to DNA. In the present study we show that TOX3 is predominantly expressed in the brain, forms homodimers and interacts with CITED1. TOX3 overexpression protects neuronal cells from cell death caused by endoplasmic reticulum stress or BAX overexpression through the induction of anti-apoptotic transcripts and repression of pro-apoptotic transcripts, which correlates with enhanced transcription involving isolated estrogen-responsive elements and estrogen-responsive promoters. However, both functions cannot be inhibited with the anti-estrogen fulvestrant and are only attenuated by mutation of estrogen-responsive elements. TOX3 also interacts with native CREB and induces the CREB-responsive BCL-2 promoter, which can be inhibited by coexpression of CITED1. Coexpression of CREB, by contrast, abolishes TOX3-mediated transcription from the estrogen-responsive complement C3 promoter. Our results suggest that TOX3 can enhance transcriptional activation from different cytoprotective promoters and that this is dependent on the predominance of either phosphorylated CREB or CITED1 within the transcriptionally active complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Survival
  • Chlorocebus aethiops
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Gene Expression Regulation
  • HEK293 Cells
  • High Mobility Group Proteins
  • Humans
  • Neurons / cytology*
  • Neurons / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation*

Substances

  • CITED1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • High Mobility Group Proteins
  • Nuclear Proteins
  • Receptors, Progesterone
  • TOX3 protein, human
  • Transcription Factors