Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure.
Bcl10, a CARD-containing protein identified from the t(1;14)(p22;q32) breakpoint in MALT lymphomas, has been shown to induce apoptosis and activate NF-kappaB in vitro. We show that one-third of bcl10-/- embryos developed exencephaly, leading to embryonic lethality. Surprisingly, bcl10-/- cells retained susceptibility to various apoptotic stimuli in vivo and in vitro. However, surviving bcl10-/- mice were severely immunodeficient and bcl10-/- lymphocytes are defective in antigen receptor or PMA/Ionomycin-induced activation. Early tyrosine phosphorylation, MAPK and AP-1 activation, and Ca2+ signaling were normal in mutant lymphocytes, but antigen receptor-induced NF-kappaB activation was absent. Thus, Bcl10 functions as a positive regulator of lymphocyte proliferation that specifically connects antigen receptor signaling in B and T cells to NF-kappaB activation.
Ruland
J
J
Amgen Institute, 620 University Avenue, Toronto, Ontario, Canada M5G 2C1.
Duncan
G S
GS
Elia
A
A
del Barco Barrantes
I
I
Nguyen
L
L
Plyte
S
S
Millar
D G
DG
Bouchard
D
D
Wakeham
A
A
Ohashi
P S
PS
Mak
T W
TW
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D000917:Antibody Formation / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001402:B-Lymphocytes / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002490:Central Nervous System / Q000002:abnormalities* / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005804:Genes, Lethal / Q000276:immunology; D007111:Immunity, Cellular / Q000276:immunology; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D009436:Neural Tube Defects / Q000276:immunology / Q000503:physiopathology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011946:Receptors, Antigen / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D019311:Staurosporine / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D011946:Receptors, Antigen; D000841:Anisomycin; D005047:Etoposide; D019311:Staurosporine; D002945:Cisplatin