Caspase-3 regulates cell cycle in B cells: a consequence of substrate specificity.
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.
Woo
Minna
M
Ontario Cancer Institute, Toronto, Ontario M5G 2N9, Canada.
Hakem
Razqallah
R
Furlonger
Caren
C
Hakem
Anne
A
Duncan
Gordon S
GS
Sasaki
Takehiko
T
Bouchard
Denis
D
Lu
Liwei
L
Wu
Gillian E
GE
Paige
Christopher J
CJ
Mak
Tak W
TW
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000276:immunology*; D002453:Cell Cycle / Q000276:immunology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000276:immunology / Q000378:metabolism; D016213:Cyclins / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013379:Substrate Specificity
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; D018844:Cyclin-Dependent Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D001973:Bromodeoxyuridine