Abstract
CBP can function as a tumor suppressor, but the mechanisms that govern oncogenesis in its absence are unknown. Here we show that CBP inactivation in mouse thymocytes leads to lymphoma. Although CBP has been implicated in the transactivation functions of p53, development of these tumors does not seem to involve loss of p53 activity. CBP-null tumors show reduced levels of p27Kip1 and increased levels of cyclin E and Skp2, two oncoproteins that can promote p27Kip1 proteolysis. Reduction of p27Kip1 by introduction of a p27Kip1-null allele into CBP knockout mice accelerates lymphomagenesis and seems to obviate the requirement for Skp2 and cyclin E upregulation. These data suggest that CBP loss mediates lymphomagenesis in cooperation with a mechanism that reduces p27Kip1 abundance.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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CREB-Binding Protein
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Cell Cycle Proteins / metabolism*
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Cloning, Molecular
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Cyclin E / metabolism
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Cyclin-Dependent Kinase Inhibitor p27
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DNA Damage / physiology
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Genes, myc / physiology
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Genetic Predisposition to Disease
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Lymphoma, T-Cell / genetics
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Lymphoma, T-Cell / metabolism*
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Microscopy, Fluorescence
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Polycomb Repressive Complex 1
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Proto-Oncogene Proteins / metabolism
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Receptors, Notch
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Repressor Proteins*
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S-Phase Kinase-Associated Proteins / metabolism
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T-Lymphocytes / metabolism*
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T-Lymphocytes / pathology
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / metabolism*
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Up-Regulation / physiology
Substances
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Bmi1 protein, mouse
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Cyclin E
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Membrane Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Receptors, Notch
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Repressor Proteins
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S-Phase Kinase-Associated Proteins
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Trans-Activators
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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CREB-Binding Protein
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Crebbp protein, mouse
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Polycomb Repressive Complex 1