Nature Immunology
4, 1016 - 1022 (2003)
Published online: 14 September 2003; | doi:10.1038/ni976
Caspase-3 regulates cell cycle in B cells: a consequence of substrate specificityMinna Woo1, 2, Razqallah Hakem3, 4, Caren Furlonger1, 4, Anne Hakem3, 4, Gordon S Duncan3, 4, Takehiko Sasaki3, 4, Denis Bouchard3, 4, Liwei Lu1, 4, 5, Gillian E Wu1, 4, 5, Christopher J Paige1, 4
& Tak W Mak3, 41
Ontario Cancer Institute, Toronto, Ontario M5G 2N9, Canada. 2
Saint Michael's Hospital, Department of Medicine, University of Toronto, Toronto M2C 2T2, Canada. 3
Advanced Medical Discovery Institute, Toronto, Ontario M5G 2C1, Canada. 4
Departments of Medical Biophysics and Immunology, University of Toronto. Toronto M5G 2N9, Canada. 5
Present addresses: Department of Pathology, The University of Hong Kong, Hong Kong, China (L.L.) and Faculty of Pure and Applied Science, York University, Toronto, Ontario M3J 1P3, Canada (G.E.W.).
Correspondence should be addressed to Tak W Mak tmak@uhnres.utoronto.caCaspases are important for apoptosis but are also involved in mammalian cell survival and cell division. Here we report that caspase-3 is a negative regulator of B cell cycling. Mice deficient in caspase-3 (Casp3-/- mice) have increased numbers of splenic B cells that show normal apoptosis but enhanced proliferation in vivo and hyperproliferation after mitogenic stimulation in vitro. Cdkn1a encodes p21 (also called Waf1 or Cip1), a cyclin-dependent kinase (CDK) inhibitor. Although expression of p21 was increased, CDK activities and proliferating cell nuclear antigen (PCNA) were increased in Casp3-/- B cells. Using Casp3-/-Cdkn1a-/- mice, we show that the hyperproliferation of Casp3-/- B cells is abolished when Cdkn1a is also deleted. Our genetic and biochemical data demonstrate that caspase-3 is essential in the regulation of B cell homeostasis.
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