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Science 12 November 1999:
Vol. 286. no. 5443, pp. 1374 - 1377
DOI: 10.1126/science.286.5443.1374
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Reports

Defective Thymocyte Maturation in p44 MAP Kinase (Erk 1) Knockout Mice

Gilles Pagès, 1* Sandrine Guérin, 2 Dominique Grall, 1 Frédéric Bonino, 1 Austin Smith, 3 Fabienne Anjuere, 2 Patrick Auberger, 2 Jacques Pouysségur 1*

The p42 and p44 mitogen-activated protein kinases (MAPKs), also called Erk2 and Erk1, respectively, have been implicated in proliferation as well as in differentiation programs. The specific role of the p44 MAPK isoform in the whole animal was evaluated by generation of p44 MAPK-deficient mice by homologous recombination in embryonic stem cells. The p44 MAPK-/- mice were viable, fertile, and of normal size. Thus, p44 MAPK is apparently dispensable and p42 MAPK (Erk2) may compensate for its loss. However, in p44 MAPK-/- mice, thymocyte maturation beyond the CD4+CD8+ stage was reduced by half, with a similar diminution in the thymocyte subpopulation expressing high levels of T cell receptor (CD3high). In p44 MAPK-/- thymocytes, proliferation in response to activation with a monoclonal antibody to the T cell receptor in the presence of phorbol myristate acetate was severely reduced even though activation of p42 MAPK was more sustained in these cells. The p44 MAPK apparently has a specific role in thymocyte development.

1 Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre A. Lacassagne, 33 Avenue de Valombrose, 06189 Nice, France.
2 Faculté de Medecine, INSERM U364 and CJF 96.05, Avenue de Valombrose, 06107 Nice, France.
3 Centre for Genome Research, King's Building, West Mains Road, Edinburgh, Scotland, UK.
*   To whom correspondence should be addressed. E-mail: gpages{at}unice.fr (G.P.) and pouysseg{at}unice.fr (J.P.)

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Analysis of gamma c-Family Cytokine Target Genes. IDENTIFICATION OF DUAL-SPECIFICITY PHOSPHATASE 5 (DUSP5) AS A REGULATOR OF MITOGEN-ACTIVATED PROTEIN KINASE ACTIVITY IN INTERLEUKIN-2 SIGNALING.
P. E. Kovanen, A. Rosenwald, J. Fu, E. M. Hurt, L. T. Lam, J. M. Giltnane, G. Wright, L. M. Staudt, and W. J. Leonard (2003)
J. Biol. Chem. 278, 5205-5213
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Restricting Zap70 Expression to CD4+CD8+ Thymocytes Reveals a T Cell Receptor-dependent Proofreading Mechanism Controlling the Completion of Positive Selection.
X. Liu, A. Adams, K. F. Wildt, B. Aronow, L. Feigenbaum, and R. Bosselut (2003)
J. Exp. Med. 197, 363-373
   Abstract »    Full Text »    PDF »
Involvement of p38 mitogen-activated protein kinase in different stages of thymocyte development.
S.-C. Hsu, C.-C. Wu, J. Han, and M.-Z. Lai (2003)
Blood 101, 970-976
   Abstract »    Full Text »    PDF »
Defective Thymocyte Maturation by Transgenic Expression of a Truncated Form of the T Lymphocyte Adapter Molecule and Fyn Substrate, Sin.
L. T. Donlin, C. A. Roman, M. Adlam, A. G. Regelmann, and K. Alexandropoulos (2002)
J. Immunol. 169, 6900-6909
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Lymphoproliferative defects in mice lacking the expression of neurofibromin: functional and biochemical consequences of Nf1 deficiency in T-cell development and function.
D. A. Ingram, L. Zhang, J. McCarthy, M. J. Wenning, L. Fisher, F.-C. Yang, D. W. Clapp, and R. Kapur (2002)
Blood 100, 3656-3662
   Abstract »    Full Text »    PDF »
ERK5 MAPK Regulates Embryonic Angiogenesis and Acts as a Hypoxia-sensitive Repressor of Vascular Endothelial Growth Factor Expression.
S. J. Sohn, B. K. Sarvis, D. Cado, and A. Winoto (2002)
J. Biol. Chem. 277, 43344-43351
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Distinct Cell Cycle Timing Requirements for Extracellular Signal-Regulated Kinase and Phosphoinositide 3-Kinase Signaling Pathways in Somatic Cell Mitosis.
E. C. Roberts, P. S. Shapiro, T. S. Nahreini, G. Pages, J. Pouyssegur, and N. G. Ahn (2002)
Mol. Cell. Biol. 22, 7226-7241
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Disruption of Mekk2 in Mice Reveals an Unexpected Role for MEKK2 in Modulating T-Cell Receptor Signal Transduction.
Z. Guo, G. Clydesdale, J. Cheng, K. Kim, L. Gan, D. J. McConkey, S. E. Ullrich, Y. Zhuang, and B. Su (2002)
Mol. Cell. Biol. 22, 5761-5768
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Thymocyte Development in Early Growth Response Gene 1-Deficient Mice.
M. Bettini, H. Xi, J. Milbrandt, and G. J. Kersh (2002)
J. Immunol. 169, 1713-1720
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Defective T cell development and function in calcineurin Abeta -deficient mice.
O. F. Bueno, E. B. Brandt, M. E. Rothenberg, and J. D. Molkentin (2002)
PNAS 99, 9398-9403
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Contributions of the T Cell Receptor-associated CD3{gamma}-ITAM to Thymocyte Selection.
M. C. Haks, E. Pepin, J. H.N. van den Brakel, S. A.A. Smeele, S. M. Belkowski, H. W.H.G. Kessels, P. Krimpenfort, and A. M. Kruisbeek (2002)
J. Exp. Med. 196, 1-13
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MEKK1 plays a critical role in activating the transcription factor C/EBP-beta -dependent gene expression in response to IFN-gamma.
S. K. Roy, J. Hu, Q. Meng, Y. Xia, P. S. Shapiro, S. P. M. Reddy, L. C. Platanias, D. J. Lindner, P. F. Johnson, C. Pritchard, et al. (2002)
PNAS 99, 7945-7950
   Abstract »    Full Text »    PDF »
Serial Triggering of T Cell Receptors Results in Incremental Accumulation of Signaling Intermediates.
Z. Borovsky, G. Mishan-Eisenberg, E. Yaniv, and J. Rachmilewitz (2002)
J. Biol. Chem. 277, 21529-21536
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Grap Negatively Regulates T-Cell Receptor-Elicited Lymphocyte Proliferation and Interleukin-2 Induction.
R. Shen, Y.-B. Ouyang, C.-K. Qu, A. Alonso, L. Sperzel, T. Mustelin, M. H. Kaplan, and G.-S. Feng (2002)
Mol. Cell. Biol. 22, 3230-3236
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Kinase Suppressor of Ras (KSR) Is a Scaffold Which Facilitates Mitogen-Activated Protein Kinase Activation In Vivo.
A. Nguyen, W. R. Burack, J. L. Stock, R. Kortum, O. V. Chaika, M. Afkarian, W. J. Muller, K. M. Murphy, D. K. Morrison, R. E. Lewis, et al. (2002)
Mol. Cell. Biol. 22, 3035-3045
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Requirement for Ca2+/Calmodulin-Dependent Kinase Type IV/Gr in Setting the Thymocyte Selection Threshold.
V. Raman, F. Blaeser, N. Ho, D. L. Engle, C. B. Williams, and T. A. Chatila (2001)
J. Immunol. 167, 6270-6278
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Duration and Strength of Extracellular Signal-Regulated Kinase Signals Are Altered During Positive Versus Negative Thymocyte Selection.
S. Mariathasan, A. Zakarian, D. Bouchard, A. M. Michie, J. C. Zuniga-Pflucker, and P. S. Ohashi (2001)
J. Immunol. 167, 4966-4973
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CD8+ Tumor-Infiltrating T Cells Are Deficient in Perforin-Mediated Cytolytic Activity Due to Defective Microtubule-Organizing Center Mobilization and Lytic Granule Exocytosis.
S. Radoja, M. Saio, D. Schaer, M. Koneru, S. Vukmanovic, and A. B. Frey (2001)
J. Immunol. 167, 5042-5051
   Abstract »    Full Text »    PDF »


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