Abstract
Genetic programs promoting cell cycle progression, DNA repair, and survival are coordinately induced in developing T cells and require rapid turnover of effector molecules. As the COP9 signalosome (CSN) has been placed at the crossroads of these programs in lower organisms, we addressed its role by conditionally deleting CSN5/JAB1, its catalytic subunit, in developing thymocytes. CSN5/JAB1(del/del) thymocytes show defective S phase progression and massive apoptosis at the double-negative (DN) 4-double-positive (DP) transition stage, which is paralleled by altered turnover of selected CSN-controlled substrates, including p53, IkappaB-alpha, and beta-catenin. Combined dysregulation of the p53 and NF-kappaB pathways affects thymocyte survival by altering the mRNA and protein levels of selected Bcl-2 family members. Genetic complementation analysis performed on p53(-/-), Bcl-xL/Bcl-2A1, or T cell receptor transgenic backgrounds indicates that CSN5/JAB1 acts at distinct developmental stages to coordinate proliferation, survival, and positive selection of thymocytes by controlling the induction of defined genetic programs acting downstream of CSN-regulated transcription factors.
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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Animals
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Apoptosis
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COP9 Signalosome Complex
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Cell Cycle
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Cell Line
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Cell Proliferation
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Cyclin-Dependent Kinase Inhibitor p16 / deficiency
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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DNA Repair
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Female
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Homeodomain Proteins / genetics
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Intracellular Signaling Peptides and Proteins / deficiency
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Multiprotein Complexes / metabolism*
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NF-kappa B / metabolism
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Peptide Hydrolases / deficiency
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Peptide Hydrolases / genetics
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Peptide Hydrolases / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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RNA, Messenger / metabolism
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Receptors, Antigen, T-Cell / metabolism
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T-Lymphocytes / cytology*
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T-Lymphocytes / metabolism
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / genetics
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Ubiquitin-Protein Ligases / metabolism
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bcl-X Protein / metabolism
Substances
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Bcl2l1 protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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Homeodomain Proteins
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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NF-kappa B
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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Receptors, Antigen, T-Cell
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Tumor Suppressor Protein p53
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bcl-X Protein
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RAG-1 protein
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Ubiquitin-Protein Ligases
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Peptide Hydrolases
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Cops5 protein, mouse
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COP9 Signalosome Complex