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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.