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Expression of activated CDC42 induces T cell apoptosis in thymus and peripheral lymph organs via different pathways

Oncogene volume 18, pages 7966–7974 (1999)Cite this article

Abstract

CDC42, a Ras-related small GTP binding protein, is involved in diverse cellular functions in lymphocytes. We generated transgenic mice expressing constitutively active murine CDC42 (Q61L) under the control of the human CD2 promoter. Transgenic mice showed smaller thymi with a dramatic reduction of CD4+CD8+, CD4+ and CD8+ thymocytes and with increase of CD4−CD8− thymocytes at CD25−CD44+ and CD25+ stage. A high percentage of the transgenic thymocytes were apoptotic, explaining the reduction of cellularity and size of the thymus. Mature T cells (TCR αβ+) in peripheral lymph organs, spleen and lymph node, were also dramatically reduced, and exhibited massive apoptosis. Expression of Fas and Fas ligand on both thymocytes and peripheral T cells was upregulated in transgenic mice, but the increased apoptosis in the thymus was independent of Fas (CD95), whereas peripheral spleen and lymph node T cell apoptosis was Fas dependent. Thus, activated CDC42 triggers distinct apoptotic pathways in thymocytes and peripheral T cells.

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Abbreviations

PCR:

polymerase chain reaction

DN:

double negative

DP:

double positive

SP:

single positive

TCR:

T cell receptor

JNK:

c-jun N-terminus kinase

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Acknowledgements

We thank C Hughes and D Butkus for help in generating transgenic mice, J Miller for technical support, T Taylor for flow cytometry, and F Manzo for help in manuscript preparation. S Na was supported by a Pfizer Inc. postdoctoral fellowship. These studies were supported by grant CA65861 and CA72009 from the National Cancer Institute (RJD). IS Grewal was an Associate, B Li is an Associate, RJ Davis and RA Flavell are Investigators of the Howard Hughes Medical Institute.

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Author notes

  1. Songqing Na and Baiyong Li: S Na and B Li contributed equally to this work

Authors and Affiliations

  1. Section of Immunobiology, Yale University School of Medicine, Connecticut, New Haven, 06520-8011, CT, USA

    Songqing Na, Baiyong Li, Iqbal S Grewal & Richard A Flavell

  2. Howard Hughes Medical Institute, New Haven, 06520, Connecticut, CT, USA

    Baiyong Li, Iqbal S Grewal & Richard A Flavell

  3. Central Research, Pfizer Inc., Groton, 06340, Connecticut, CT, USA

    Songqing Na & Jeffrey H Hanke

  4. Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, 01605, Massachusetts, MA, USA

    Hervé Enslen & Roger J Davis

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Na, S., Li, B., Grewal, I. et al. Expression of activated CDC42 induces T cell apoptosis in thymus and peripheral lymph organs via different pathways. Oncogene 18, 7966–7974 (1999). https://doi.org/10.1038/sj.onc.1203122

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