Tristetraprolin Impairs Myc-Induced Lymphoma and Abolishes the Malignant State

SummaryMyc 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.

Graphical AbstractFigure optionsDownload high-quality image (189 K)Download as PowerPoint slideHighlights
► Myc controls levels of ARE-containing mRNAs via select AU-binding proteins (AUBPs)
► Repression of the AUBP tristetraprolin (TTP) is a hallmark of MYC-dependent tumors
► TTP is a tumor suppressor that impairs development and maintenance of lymphoma
► Myc/TTP-directed control of select cancer genes is disabled during lymphomagenesis