title: Tristetraprolin impairs myc-induced lymphoma and abolishes the malignant state.
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.
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Rounbehler
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi
authors.forename: Chunying
authors.initials: C
authors.lastname: Yang
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Steeves
authors.forename: Weimin
authors.initials: W
authors.lastname: Li
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Doherty
authors.forename: Franz X
authors.initials: FX
authors.lastname: Schaub
authors.forename: Sandhya
authors.initials: S
authors.lastname: Sanduja
authors.forename: Dan A
authors.initials: DA
authors.lastname: Dixon
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry; D051816:Tristetraprolin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C541099:TTP protein, mouse; D051816:Tristetraprolin; C497552:ZFP36 protein, human