Abstract
Ras GTPase-activating proteins (RasGAPs) inhibit signal transduction initiated through the Ras small GTP-binding protein. However, which members of the RasGAP family act as negative regulators of T cell responses is not completely understood. In this study, we investigated potential roles for the RasGAPs RASA1 and neurofibromin 1 (NF1) in T cells through the generation and analysis of T cell-specific RASA1 and NF1 double-deficient mice. In contrast to mice lacking either RasGAP alone in T cells, double-deficient mice developed T cell acute lymphoblastic leukemia/lymphoma, which originated at an early point in T cell development and was dependent on activating mutations in the Notch1 gene. These findings highlight RASA1 and NF1 as cotumor suppressors in the T cell lineage.
Copyright © 2015 by The American Association of Immunologists, Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Gene Deletion
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Gene Expression Regulation
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Mice
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Mice, Knockout
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Mutation
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Neurofibromin 1 / deficiency
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Neurofibromin 1 / genetics*
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Neurofibromin 1 / immunology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / mortality
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Receptor, Notch1 / genetics*
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Receptor, Notch1 / immunology
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Signal Transduction
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Spleen / immunology
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Spleen / pathology
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Survival Analysis
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T-Lymphocytes / immunology
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T-Lymphocytes / pathology
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Thymus Gland / immunology
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Thymus Gland / pathology
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Time Factors
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p120 GTPase Activating Protein / deficiency
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p120 GTPase Activating Protein / genetics*
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p120 GTPase Activating Protein / immunology
Substances
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Neurofibromin 1
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Notch1 protein, mouse
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RASA1 protein, mouse
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Receptor, Notch1
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p120 GTPase Activating Protein