Retinoic acid induces TGFbeta-dependent autocrine fibroblast growth

Oncogene. 2008 Jan 17;27(4):477-89. doi: 10.1038/sj.onc.1210657. Epub 2007 Jul 16.

Abstract

To evaluate the role of murine TFIID subunit TAF4 in activation of cellular genes by all-trans retinoic acid (T-RA), we have characterized the T-RA response of taf4(lox/-) and taf4(-/-) embryonic fibroblasts. T-RA regulates almost 1000 genes in taf4(lox/-) cells, but less than 300 in taf4(-/-) cells showing that TAF4 is required for T-RA regulation of most, but not all cellular genes. We further show that T-RA-treated taf4(lox/-) cells exhibit transforming growth factor (TGF)beta-dependent autocrine growth and identify a set of genes regulated by loss of TAF4 and by T-RA corresponding to key mediators of the TGFbeta signalling pathway. T-RA rapidly and potently induces expression of connective tissue growth factor (CTGF) via a conserved DR2 type response element in its proximal promoter leading to serum-free autocrine growth. These results highlight the role of TAF4 as a cofactor in the cellular response to T-RA and identify the genetic programme of a novel cross talk between the T-RA and TGFbeta pathways that leads to deregulated cell growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication / drug effects*
  • Autocrine Communication / genetics
  • Base Sequence
  • COS Cells
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Chlorocebus aethiops
  • Connective Tissue Growth Factor
  • Consensus Sequence
  • Fibroblasts / drug effects*
  • Fibroblasts / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Immediate-Early Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / genetics
  • Mice
  • Receptor Cross-Talk / drug effects
  • Receptors, Retinoic Acid / metabolism
  • Response Elements
  • Transcription Factor TFIID / genetics
  • Transcription Factor TFIID / metabolism
  • Transcription Factor TFIID / physiology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology*
  • Tretinoin / pharmacology*

Substances

  • CCN2 protein, mouse
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Receptors, Retinoic Acid
  • TAF4 protein, mouse
  • Transcription Factor TFIID
  • Transforming Growth Factor beta
  • retinoic acid receptor gamma
  • Connective Tissue Growth Factor
  • Tretinoin