Activation of p38 MAP kinase by DNA double-strand breaks in V(D)J recombination induces a G2/M cell cycle checkpoint.
Delay of cell cycle progression in response to double-strand DNA breaks (DSBs) is critical to allow time for DNA repair and prevent cellular transformation. Here, we show that the p38 mitogen-activated protein (MAP) kinase signaling pathway is activated in immature thymocytes along with TcRbeta gene V(D)J recombination. Active p38 MAP kinase promotes a G2/M cell cycle checkpoint through the phosphorylation and activation of p53 in these cells in vivo. Inactivation of p38 MAP kinase and p53 is required for DN3 thymocytes to exit the G2/M checkpoint, progress through mitosis and further differentiate. We propose that p38 MAP kinase is activated by V(D)J-mediated DSBs and induces a p53-mediated G2/M checkpoint to allow DNA repair and prevent cellular transformation.
Pedraza-Alva
Gustavo
G
Department of Medicine/Immunobiology Program, University of Vermont, Burlington, VT 05405, USA.
Koulnis
Miroslav
M
Charland
Colette
C
Thornton
Tina
T
Clements
James L
JL
Schlissel
Mark S
MS
Rincón
Mercedes
M
D000818:Animals; D002455:Cell Division / Q000276:immunology; D004249:DNA Damage / Q000276:immunology*; D004260:DNA Repair / Q000502:physiology; D016195:G2 Phase / Q000276:immunology; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases