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© The Rockefeller University Press, 0022-1007/1999/3/957/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 6, March 15, 1999 957-968

Articles

The Cyclin-dependent Kinase Cdk2 Regulates Thymocyte Apoptosis

Anne Hakem, Takehiko Sasaki, Ivona Kozieradzki, and Josef M. Penninger

From The Amgen Institute, the Ontario Cancer Institute, and the Department of Medical Biophysics and the Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5G 2C1

Aberrant activation of cell cycle molecules has been postulated to play a role in apoptosis ("catastrophic cell cycle"). Here we show that in noncycling developing thymocytes, the cyclin- dependent kinase Cdk2 is activated in response to all specific and nonspecific apoptotic stimuli tested, including peptide-specific thymocyte apoptosis. Cdk2 was found to function upstream of the tumor suppressor p53, transactivation of the death promoter Bax, alterations of mitochondrial permeability, Bcl-2, caspase activation, and caspase-dependent proteolytic cleavage of the retinoblastoma protein. Inhibition of Cdk2 completely protected thymocytes from apoptosis, mitochondrial changes, and caspase activation. These data provide the first evidence that Cdk2 activity is crucial for the induction of thymocyte apoptosis.

Key Words: cyclin-dependent kinase 2 • apoptosis • cell cycle • thymocyte

Address correspondence to Josef M. Penninger, The Amgen Institute, 620 University Ave., Suite 706, Toronto, Ontario, Canada M5G 2C1. Phone: 416-204-2241; Fax: 416-204-2278; E-mail: jpenning{at}amgen.com

A. Hakem and J.M. Penninger are supported by a grant from the Medical Research Council of Canada.

Abbreviations used: aa, amino acid(s); Cdk, cyclin-dependent kinase; {Delta}{Psi}m, mitochondrial transmembrane potential; FTOC, fetal thymic organ culture; GST, glutathione S-transferase; LCMV, lympholytic choriomeningitis virus; PI, propidium iodide; PK, protein kinase; Rb, retinoblastoma protein; Tg, transgenic.


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