Tripartite motif 24 (Trim24/Tif1α) tumor suppressor protein is a novel negative regulator of interferon (IFN)/signal transducers and activators of transcription (STAT) signaling pathway acting through retinoic acid receptor α (Rarα) inhibition

J Biol Chem. 2011 Sep 23;286(38):33369-79. doi: 10.1074/jbc.M111.225680. Epub 2011 Jul 18.


Recent genetic studies in mice have established that the nuclear receptor coregulator Trim24/Tif1α suppresses hepatocarcinogenesis by inhibiting retinoic acid receptor α (Rara)-dependent transcription and cell proliferation. However, Rara targets regulated by Trim24 remain unknown. We report that the loss of Trim24 resulted in interferon (IFN)/STAT pathway overactivation soon after birth (week 5). Despite a transient attenuation of this pathway by the induction of several IFN/STAT pathway repressors later in the disease, this phenomenon became more pronounced in tumors. Remarkably, Rara haplodeficiency, which suppresses tumorigenesis in Trim24(-/-) mice, prevented IFN/STAT overactivation. Moreover, together with Rara, Trim24 bound to the retinoic acid-responsive element of the Stat1 promoter and repressed its retinoic acid-induced transcription. Altogether, these results identify Trim24 as a novel negative regulator of the IFN/STAT pathway and suggest that this repression through Rara inhibition may prevent liver cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Cluster Analysis
  • Gene Dosage
  • Gene Expression Regulation / drug effects
  • Humans
  • Interferons / metabolism*
  • Liver / drug effects
  • Liver / metabolism
  • Liver Neoplasms / genetics
  • Mice
  • Models, Biological
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / metabolism*
  • Receptors, Retinoic Acid / antagonists & inhibitors*
  • Receptors, Retinoic Acid / metabolism
  • Reproducibility of Results
  • Retinoic Acid Receptor alpha
  • STAT Transcription Factors / metabolism*
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • Transcription Factors / deficiency
  • Transcription Factors / metabolism*
  • Transcriptome
  • Tretinoin / pharmacology


  • Nuclear Proteins
  • RARA protein, human
  • Rara protein, mouse
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • STAT Transcription Factors
  • Transcription Factors
  • transcriptional intermediary factor 1
  • Tretinoin
  • Interferons