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Tristetraprolin Impairs Myc-Induced Lymphoma and Abolishes the Malignant State
- Rounbehler, Robert J., Fallahi, Mohammad, Yang, Chunying, Steeves, Meredith A., Li, Weimin, Doherty, Joanne R., Schaub, Franz X., Sanduja, Sandhya, Dixon, Dan A., Blackshear, Perry J., Cleveland, John L.
- Cell 2012 v.150 no.3 pp. 563-574
- carcinogenesis, genes, interleukin-7, lymphoma, messenger RNA, oncogene proteins
- 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.