Tristetraprolin Impairs Myc-Induced Lymphoma and Abolishes the Malignant State
Menée in vitro, cette étude montre que la tristétrapoline joue un rôle de suppresseur de tumeurs dans les lymphomes induits par l'oncoprotéine Myc
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. º Myc controls levels of ARE-containing mRNAs via select AU-binding proteins (AUBPs) º Repression of the AUBP tristetraprolin (TTP) is a hallmark of MYC-dependent tumors º TTP is a tumor suppressor that impairs development and maintenance of lymphoma º Myc/TTP-directed control of select cancer genes is disabled during lymphomagenesis Myc oncoproteins regulate the transcription of several AU-binding proteins, thus indirectly regulating multiple AU-containing mRNAs. Activation of one such AUBP, Tristetraprolin (TTP), counteracts the development and maintenance of Myc-induced lymphoma, establishing TTP as a tumor suppressor and a potential target for therapeutic intervention.
Cell 2012