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Originally published In Press as doi:10.1074/jbc.M203553200 on July 11, 2002

J. Biol. Chem., Vol. 277, Issue 42, 39156-39162, October 18, 2002
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Molecular Mechanisms of Pre-T Cell Receptor-induced Survival*

Cristina MurgaDagger § and Domingo F. Barber§||

From the Dagger  Centro de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain and the || Department of Immunology and Oncology, Centro Nacional de Biotecnología, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain

En route to maturing as T cell receptor (TCR) alpha beta -expressing cells, the development of thymocytes is contingent on expression of a pre-TCR complex comprising a TCRbeta chain paired with a surrogate TCRalpha chain, pre-Talpha (pTalpha ). The pre-TCR has been proposed to promote cell survival, proliferation, differentiation, and lineage commitment. However, the precise molecular mechanisms governing this variety of effects remain elusive. Here, we present a cellular system designed to biochemically dissect signals elicited upon pre-TCR expression. Using the T cell line 4G4 stably transfected with one of the two known pTalpha isoforms or selective pTalpha deletion mutants and TCRbeta , we were able to observe that expression of a functional pre-TCR complex is sufficient to control the levels of surface Fas protein, the stimulation of mitogen-activated and stress-regulated kinases, and the activation status of the p53 antioncogene. We demonstrate that this regulation has a major impact on the expression of important regulators of apoptosis, such as Bcl-2 family members, and the cell cycle, such as p21WAF. Furthermore, we show here that cells expressing a functional pre-TCR are more resistant to different types of DNA damage-induced apoptosis and that these effects are contingent on an intact cytoplasmic tail of pTalpha . We finally propose that the presence of a functional pre-TCR complex triggers many intracellular pathways capable of driving and ensuring thymocyte survival in the presence of DNA damage.

* This work was supported in part by grants from the Spanish Research Council and the Pharmacia Corporation to the Department of Immunology and Oncology. We gratefully acknowledge the institutional support of the "Fundación Ramón Areces" to the Centro de Biología Molecular and the help from Dr. Federico Mayor, Jr.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This work is dedicated to the memory of the late Jesús Murga, Sr.

§ Recipients of grants by the Spanish Ministerio de Ciencia y Tecnología (Ramón y Cajal Programme).

To whom correspondence should be addressed: Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid 28049, Spain. E-mail: cmurga@cbm.uam.es.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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