Survivin loss in thymocytes triggers p53-mediated growth arrest and p53-independent cell death.
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.
Okada
Hitoshi
H
Advanced Medical Discovery Institute, University of Toronto, 620 University Avenue, Suite 706, Ontario M5G 2C1, Canada. hokada@uhnres.utoronto.ca
Bakal
Chris
C
Shahinian
Arda
A
Elia
Andrew
A
Wakeham
Andrew
A
Suh
Woong-Kyung
WK
Duncan
Gordon S
GS
Ciofani
Maria
M
Rottapel
Robert
R
Zúñiga-Pflücker
Juan Carlos
JC
Mak
Tak W
TW
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D005434:Flow Cytometry; D051034:Inhibitor of Apoptosis Proteins; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53