Abstract
ZFP36L1 and ZFP36L2 are RNA-binding proteins (RBPs) that interact with AU-rich elements in the 3' untranslated region of mRNA, which leads to mRNA degradation and translational repression. Here we show that mice that lacked ZFP36L1 and ZFP36L2 during thymopoiesis developed a T cell acute lymphoblastic leukemia (T-ALL) dependent on the oncogenic transcription factor Notch1. Before the onset of T-ALL, thymic development was perturbed, with accumulation of cells that had passed through the beta-selection checkpoint without first expressing the T cell antigen receptor beta-chain (TCRbeta). Notch1 expression was higher in untransformed thymocytes in the absence of ZFP36L1 and ZFP36L2. Both RBPs interacted with evolutionarily conserved AU-rich elements in the 3' untranslated region of Notch1 and suppressed its expression. Our data establish a role for ZFP36L1 and ZFP36L2 during thymocyte development and in the prevention of malignant transformation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Butyrate Response Factor 1
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Conserved Sequence
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Humans
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Immunophenotyping
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Kaplan-Meier Estimate
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Mice
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Mice, Knockout
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Molecular Sequence Data
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Nuclear Proteins / deficiency*
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / immunology*
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / immunology
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Receptor, Notch1 / genetics
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Receptor, Notch1 / immunology
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Sequence Alignment
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T-Lymphocytes / immunology*
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Thymus Gland / growth & development
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Thymus Gland / immunology*
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Transcription, Genetic
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Tristetraprolin / deficiency*
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Tristetraprolin / genetics
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Tristetraprolin / immunology
Substances
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Butyrate Response Factor 1
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Notch1 protein, mouse
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Nuclear Proteins
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RNA-Binding Proteins
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Receptor, Notch1
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Receptors, Antigen, T-Cell
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Tristetraprolin
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Zfp36 protein, mouse
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Zfp36l1 protein, mouse