Targeted inactivation of the COP9 signalosome impairs multiple stagesof T cell development

• DOI: 10.1084/jem.20070725
• Publication Date: 2008-02-12T17:27:13Z
• Authors: Martina Panattoni; Francesca Sanvito; Veronica Basso; Claudio Doglioni; Giulia Casorati; Eugenio Montini; Jeffrey R. Bender; Anna Mondino; Ruggero Pardi
• Keywords: Homeodomain Proteins; Mice, Knockout; 0301 basic medicine; DNA Repair; COP9 Signalosome Complex; Cell Cycle; Intracellular Signaling Peptides and Proteins; NF-kappa B; Receptors, Antigen, T-Cell; Apoptosis; Articles; Cell Line; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Proto-Oncogene Proteins c-bcl-2; Multiprotein Complexes; Animals; Female; RNA, Messenger; Cyclin-Dependent Kinase Inhibitor p16; Cell Proliferation; Peptide Hydrolases

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/JAB1del/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, IκB-α, and β-catenin. Combined dysregulation of the p53 and NF-κB 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.