Abstract
Caspases 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / immunology
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B-Lymphocytes / cytology
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B-Lymphocytes / enzymology
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B-Lymphocytes / immunology*
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Bromodeoxyuridine / metabolism
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Caspase 3
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Caspases / genetics
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Caspases / immunology*
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Cell Cycle / immunology
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinases / immunology
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Cyclin-Dependent Kinases / metabolism
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Cyclins / biosynthesis
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Cyclins / immunology
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Flow Cytometry
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Immunohistochemistry
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Proliferating Cell Nuclear Antigen / biosynthesis
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Proliferating Cell Nuclear Antigen / immunology
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Spleen / immunology
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Spleen / pathology
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Substrate Specificity
Substances
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Proliferating Cell Nuclear Antigen
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Cyclin-Dependent Kinases
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Casp3 protein, mouse
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Caspase 3
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Caspases
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Bromodeoxyuridine