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

Tristetraprolin impairs myc-induced lymphoma and abolishes the malignant state.

Author information

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

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.

PMID:
22863009
PMCID:
PMC3422762
DOI:
10.1016/j.cell.2012.06.033
[Indexed for MEDLINE]
Free PMC Article

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