Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [retrovirally infected ex vivo lymphoma]

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. Ex vivo Eμ-Myc lymphoma cells were infected with MSCV-I-dsRed2 (RFP) and FACS sorted for dsRed2+ cells. These cells were then infected with MSCV-TTP-I-GFP and FACS sorted for GFP expression (TTP-GFP- or TTP-GFP+). These cells were used for subsequent RNA purification, labeling and hybridization to MOE430 2.0 Affymetrix arrays.

ORGANISM(S): Mus musculus

SUBMITTER: John Cleveland 

PROVIDER: E-GEOD-37791 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress