Activation of the p38 mitogen-activated protein kinase pathway arrests cell cycle progression and differentiation of immature thymocytes in vivo.
The development of T cells in the thymus is coordinated by cell-specific gene expression programs that involve multiple transcription factors and signaling pathways. Here, we show that the p38 mitogen-activated protein (MAP) kinase signaling pathway is strictly regulated during the differentiation of CD4(-)CD8(-) thymocytes. Persistent activation of p38 MAP kinase blocks fetal thymocyte development at the CD25(+)CD44(-) stage in vivo, and results in the lack of T cells in the peripheral immune system of adult mice. Inactivation of p38 MAP kinase is required for further differentiation of these cells into CD4(+)CD8(+) thymocytes. The arrest of cell cycle in mitosis is partially responsible for the blockade of differentiation. Therefore, the p38 MAP kinase pathway is a critical regulatory element of differentiation and proliferation during the early stages of in vivo thymocyte development.
Diehl
N L
NL
Immunobiology Program, Department of Medicine, University of Vermont, Burlington, Vermont 05405, USA.
Enslen
H
H
Fortner
K A
KA
Merritt
C
C
Stetson
N
N
Charland
C
C
Flavell
R A
RA
Davis
R J
RJ
Rincón
M
M
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002453:Cell Cycle; D002454:Cell Differentiation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018960:Hyaluronan Receptors / Q000276:immunology; D007093:Imidazoles / Q000494:pharmacology; D008221:Lymphoid Tissue / Q000166:cytology; D048669:MAP Kinase Kinase 6; D020935:MAP Kinase Signaling System; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; D007093:Imidazoles; D011725:Pyridines; D015375:Receptors, Interleukin-2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482567:Map2k6 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580