The Journal of Experimental Medicine
Randox
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Published online February 11, 2008
doi:10.1084/jem.20070725
The Journal of Experimental Medicine, Vol. 205, No. 2, 465-477
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Panattoni et al.
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ARTICLE

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

Martina Panattoni1,2, Francesca Sanvito2, Veronica Basso2, Claudio Doglioni1,2, Giulia Casorati2, Eugenio Montini3, Jeffrey R. Bender4, Anna Mondino2, and Ruggero Pardi1,2

1 Vita-Salute San Raffaele University School of Medicine, 20132 Milano, Italy
2 Department of Biological and Technological Research, Scientific Institute San Raffaele, 20132 Milano, Italy
3 San Raffaele-Telethon Institute for Gene Therapy, 20132 Milano, Italy
4 Raymond and Beverly Sackler Foundation Cardiovascular Laboratory, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT 06520

CORRESPONDENCE Ruggero Pardi:pardi.ruggero{at}hsr.it

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, I{kappa}B-{alpha}, and β-catenin. Combined dysregulation of the p53 and NF-{kappa}B 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.

Abbreviations used: ClC, cleaved effector caspase; CSN, COP9 signalosome; DN, double-negative; DP, double-positive; HRP, horseradish peroxidase; ISP, intermediate single-positive; PI, propidium iodide; SP, single-positive; UPS, ubiquitin-proteasome system.


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