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Tristetraprolin impairs myc-induced lymphoma and abolishes the malignant state

Robert J Rounbehler1, Mohammad Fallahi, Chunying Yang

  • 1Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.

Cell
|August 7, 2012
PubMed

Insights

Myc oncoprotein affects gene expression by regulating mRNA turnover through AU-binding proteins (AUBPs). Suppressing Tristetraprolin (TTP) is key to Myc-driven cancers, with TTP acting as a tumor suppressor.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • Myc oncoproteins influence gene transcription, but a significant portion of Myc-regulated genes involves post-transcriptional mechanisms.
  • mRNA turnover is modulated by AU-binding proteins (AUBPs) that interact with AU-rich elements (AREs) in transcripts.
  • Understanding Myc's impact on AUBPs and ARE-containing (ARED) genes is crucial for deciphering its role in tumorigenesis.

Purpose of the Study:

  • To investigate how Myc oncoproteins regulate mRNA turnover via AUBPs and ARED genes.
  • To determine the role of Tristetraprolin (TTP/ZFP36), an AUBP, in Myc-driven lymphomagenesis.
  • To elucidate the mechanism by which Myc influences TTP expression and its consequences in cancer.

Main Methods:

  • Analysis of precancerous and malignant Myc-expressing B cells.
  • Assessment of Myc's direct transcriptional regulation of TTP and other ARED genes.
  • Evaluation of TTP's function in Myc-induced lymphomagenesis and cancer maintenance.

Main Results:

  • Myc regulates hundreds of ARED genes and specific AUBPs in B cells.
  • Myc directly suppresses the transcription of the mRNA-destabilizing AUBP, Tristetraprolin (TTP).
  • TTP suppression is a hallmark of MYC-involved cancers, and its restoration inhibits lymphomagenesis, indicating TTP acts as a tumor suppressor.

Conclusions:

  • Myc utilizes AUBPs, particularly TTP, to control ARED genes involved in tumorigenesis.
  • The suppression of TTP by Myc is a critical circuit in B lymphopoiesis and IL7 signaling, and its dysregulation is selected for in malignancy.
  • Targeting the Myc-TTP axis offers potential therapeutic strategies for MYC-driven cancers.

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