Regulatory mechanisms of TRAF2-mediated signal transduction by Bcl10, a MALT lymphoma-associated protein.
To elucidate the function of Bcl10, recently cloned as an apoptosis-associated gene mutated in MALT lymphoma, we identified its binding partner TRAF2, which mediates signaling via tumor necrosis factor receptors. In mammalian cells, low levels of Bcl10 expression promoted the binding of TRAF2 and c-IAPs. Conversely, excessive expression inhibited complex formation. Overexpressed Bcl10 reduced c-Jun N-terminal kinase activation and induced nuclear factor kappaB activation downstream of TRAF2. To determine whether overexpression of Bcl10 could perturb the regulation of apoptosis in vivo, we generated Bcl10 transgenic mice. In these transgenic mice, atrophy of the thymus and spleen was observed at postnatal stages. The morphological changes in these tissues were caused by acceleration of apoptosis in T cells and B cells. The phenotype of Bcl10 transgenic mice was similar to that of TRAF2-deficient mice reported previously, indicating that excessive expression of Bcl10 might deplete the TRAF2 function. In contrast, in the other organs such as the brain, where Bcl10 was expressed at high levels, no apoptosis was detected. The altered sensitivities to overexpressed Bcl10 may have been due to differences in signal responses to Bcl10 among cell types. Thus, Bcl10 was suggested to play crucial roles in the modulation of apoptosis associated with TRAF2.
Yoneda
T
T
Department of Anatomy, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. yoneda@anat2.med.osaka-u.ac.jp
Imaizumi
K
K
Maeda
M
M
Yui
D
D
Manabe
T
T
Katayama
T
T
Sato
N
N
Gomi
F
F
Morihara
T
T
Mori
Y
Y
Miyoshi
K
K
Hitomi
J
J
Ugawa
S
S
Yamada
S
S
Okabe
M
M
Tohyama
M
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001483:Base Sequence; D004789:Enzyme Activation; D051034:Inhibitor of Apoptosis Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D014764:Viral Proteins / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D014764:Viral Proteins; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases