The Journal of Experimental Medicine
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Published 2 February 2004. doi:10.1084/jem.20032092
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 3, 399-410
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Survivin Loss in Thymocytes Triggers p53-mediated Growth Arrest and p53-independent Cell Death

Hitoshi Okada1,2, Chris Bakal2,4, Arda Shahinian1,2, Andrew Elia1,2, Andrew Wakeham1,2, Woong-Kyung Suh1,2, Gordon S. Duncan1,2, Maria Ciofani4,5, Robert Rottapel2,4, Juan Carlos Zúñiga-Pflücker4,5, and Tak W. Mak1,2,3,4

1 Advanced Medical Discovery Institute, University of Toronto, Toronto, Ontario M5G 2C1, Canada
2 Ontario Cancer Institute, University of Toronto, Toronto, Ontario M5G 2C1, Canada
3 Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada
4 Department of Immunology, University of Toronto, Toronto, Ontario M5G 2C1, Canada
5 Sunnybrook and Women's College Health Sciences Center, Toronto, Ontario M4N 3M5, Canada

Address correspondence to Tak W. Mak, Advanced Medical Discovery Institute, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada. Phone: (416) 946-2234; Fax: (416) 204-5300; email: tmak{at}uhnres.utoronto.ca; or Hitoshi Okada, Advanced Medical Discovery Institute, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2C1, Canada. Phone: (416) 946-4501; Fax: (416) 204-2278; email: hokada{at}uhnres.utoronto.ca

Because survivin-null embryos die at an early embryonic stage, the role of survivin in thymocyte development is unknown. We have investigated the role by deleting the survivin gene only in the T lineage and show here that loss of survivin blocks the transition from CD4- CD8- double negative (DN) thymocytes to CD4+ CD8+ double positive cells. Although the pre–T cell receptor signaling pathway is intact in survivin-deficient thymocytes, the cells cannot respond to its signals. In response to proliferative stimuli, cycling survivin-deficient DN cells exhibit cell cycle arrest, a spindle formation defect, and increased cell death. Strikingly, loss of survivin activates the tumor suppressor p53. However, the developmental defects caused by survivin deficiency cannot be rescued by p53 inactivation or introduction of Bcl-2. These lines of evidence indicate that developing thymocytes depend on the cytoprotective function of survivin and that this function is tightly coupled to cell proliferation but independent of p53 and Bcl-2. Thus, survivin plays a critical role in early thymocyte development.

Key Words: pre–T cell • cell death • development • thymus • mitosis

C. Bakal and A. Shahinian contributed equally to this work.

Abbreviations used in this paper: 7AAD, 7-amino actinomycin D; DN, double negative; DP, double positive; ERK, extracellular signal–regulated kinase; ES, embryonic stem; HSA, heat stable antigen; Lin, lineage marker; SP, single positive.


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