Tristetraprolin Impairs Myc-Induced Lymphoma and Abolishes the Malignant State

Cell. 2012 Aug 3;150(3):563-74. doi: 10.1016/j.cell.2012.06.033.

Abstract

Myc oncoproteins directly regulate transcription by binding to target genes, yet this only explains a fraction of the genes affected by Myc. mRNA turnover is controlled via AU-binding proteins (AUBPs) that recognize AU-rich elements (AREs) found within many transcripts. Analyses of precancerous and malignant Myc-expressing B cells revealed that Myc regulates hundreds of ARE-containing (ARED) genes and select AUBPs. Notably, Myc directly suppresses transcription of Tristetraprolin (TTP/ZFP36), an mRNA-destabilizing AUBP, and this circuit is also operational during B lymphopoiesis and IL7 signaling. Importantly, TTP suppression is a hallmark of cancers with MYC involvement, and restoring TTP impairs Myc-induced lymphomagenesis and abolishes maintenance of the malignant state. Further, there is a selection for TTP loss in malignancy; thus, TTP functions as a tumor suppressor. Finally, Myc/TTP-directed control of select cancer-associated ARED genes is disabled during lymphomagenesis. Thus, Myc targets AUBPs to regulate ARED genes that control tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • B-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Genes, Tumor Suppressor*
  • HeLa Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lymphoma, B-Cell / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Stability
  • RNA, Messenger / chemistry
  • Tristetraprolin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • TTP protein, mouse
  • Tristetraprolin
  • ZFP36 protein, human