Author/Authors :
Robert J. Rounbehler، نويسنده , , Mohammad Fallahi Moghimi، نويسنده , , Chunying Yang، نويسنده , , Meredith A. Steeves، نويسنده , , Weimin Li، نويسنده , , Joanne R. Doherty، نويسنده , , Franz X. Schaub، نويسنده , , Sandhya Sanduja، نويسنده , , Dan A. Dixon، نويسنده , , Perry J. Blackshear، نويسنده , , John L. Cleveland، نويسنده ,
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.