期刊
NATURE
卷 459, 期 7247, 页码 712-U118出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature07969
关键词
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资金
- Core Research for Evolutional Science and Technology
- Japan Science and Technology Agency
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Ministry of Health, Labor and Welfare of Japan
- Grants-in-Aid for Scientific Research [21390316] Funding Source: KAKEN
A20 is a negative regulator of the NF-kappa B pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation(1). It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappa B in response to a variety of external stimuli(2-7); recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk(8,9). However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of ;nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wildtype A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by down-regulation of NF-kappa B activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappa B activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappa B activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappa B caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.
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