Selective Expansion of Marginal Zone B Cells in Eμ-API2-MALT1 Mice Is Linked to Enhanced IκB Kinase γ Polyubiquitination
- 15 May 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 66 (10), 5270-5277
- https://doi.org/10.1158/0008-5472.can-05-4590
Abstract
The translocation t(11;18)(q21;q21) that generates an API2-MALT1 fusion protein is the most common structural abnormality among the genetic defects reported in mucosa-associated lymphoid tissue (MALT)-type lymphomas, and its presence correlates with the apparent lack of further genetic instability or chromosomal imbalances. Hence, constitutive nuclear factor-κB (NF-κB) activation induced by the API2-MALT1 fusion protein is considered essential for B-cell transformation. To examine its role in B-cell development and lymphomagenesis, Eμ-API2-MALT1 transgenic mice were produced. Our data show that expression of the API2-MALT1 fusion protein alone is not sufficient for the development of lymphoma masses within 50 weeks. Nevertheless, API2-MALT1 expression affected B-cell maturation in the bone marrow and triggered the specific expansion of splenic marginal zone B cells. Polyubiquitination of IκB kinase γ (IKKγ), indicative for enhanced NF-κB activation, was increased in splenic lymphocytes and promoted the survival of B cells ex vivo. In addition, we show that the API2-MALT1 fusion resided in the cholesterol- and sphingolipid-enriched membrane microdomains, termed lipid rafts. We provide evidence that association of the MALT1 COOH terminal with the lipid rafts, which is mediated by the API2 portion, is sufficient to trigger NF-κB activation via enhanced polyubiquitination of IKKγ. Taken together, these data support the hypothesis that the API2-MALT1 fusion protein can contribute to MALT lymphoma formation via increased NF-κB activation. (Cancer Res 2006; 66(10): 5270-7)Keywords
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This publication has 36 references indexed in Scilit:
- MALT1 contains nuclear export signals and regulates cytoplasmic localization of BCL10Blood, 2005
- API2-MALT1 fusion protein induces transcriptional activation of the API2 gene through NF-κB binding elements: Evidence for a positive feed-back loop pathway resulting in unremitting NF-κB activationBiochemical and Biophysical Research Communications, 2005
- Control of lymphocyte development by nuclear factor-κBNature Reviews Immunology, 2005
- Constitutive NF-κB activation by the t(11;18)(q21;q21) product in MALT lymphoma is linked to deregulated ubiquitin ligase activityCancer Cell, 2005
- MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-κB-dependent proliferative advantage and resistance against FAS-induced cell death in B cellsBlood, 2005
- MALT1/Paracaspase Is a Signaling Component Downstream of CARMA1 and Mediates T Cell Receptor-induced NF-κB ActivationJournal of Biological Chemistry, 2004
- Regulation of NF-κB-Dependent Lymphocyte Activation and Development by ParacaspaseScience, 2003
- Stability and subcellular localization of API2-MALT1 chimeric protein involved in t(11;18) (q21;q21) MALT lymphomaOncogene, 2003
- MALT LymphomasHematology-American Society Hematology Education Program, 2001
- B cell precursor growth-promoting activity. Purification and characterization of a growth factor active on lymphocyte precursors.The Journal of Experimental Medicine, 1988