MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF- B–dependent proliferative advantage and resistance against FAS-induced cell death in B cells
نویسندگان
چکیده
The most frequently recurring translocations in mucosa-associated lymphoid tissue (MALT) B-cell non-Hodgkin lymphoma, t(11;18)(q21;q21) and t(14;18)(q32; q21), lead to formation of an API2-MALT1 fusion or IgH-mediated MALT1 overexpression. Various approaches have implicated these proteins in nuclear factor B (NFB) signaling, but this has not been shown experimentally in human B cells. Immunohistochemistry showed that MALT1 is predominantly expressed in normal and malignant germinal center B cells, corresponding to the differentiation stage of MALT lymphoma. We expressed MALT1 and apoptosis inhibitor-2 API2/MALT1 in human B-cell lymphoma BJAB cells and found both transgenes in membrane lipid rafts along with endogenous MALT1 and 2 binding partners involved in NFB signaling, B-cell lymphoma 10 (BCL10) and CARMA1 (caspase recruitment domain [CARD]–containing membrane-associated guanylate kinase [MAGUK] 1). API2MALT1 and exogenous MALT1 increased constitutive NFB activity and enhanced I B kinase (IKK) activation induced by CD40 stimulation. Both transgenes protected BJAB cells from FAS (CD95)– induced death, consistent with increases in NFB cytoprotective target gene expression, and increased their proliferation rate. Expression of a dominant-negative I B mutant showed that these survival and proliferative advantages are dependent on elevated constitutive NFB activity. Our findings support a model in which NFB signaling, once activated in a CD40dependent immune response, is maintained and enhanced through deregulation of MALT1 or formation of an API2MALT1 fusion. (Blood. 2005;105:2891-2899)
منابع مشابه
MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells.
The most frequently recurring translocations in mucosa-associated lymphoid tissue (MALT) B-cell non-Hodgkin lymphoma, t(11;18)(q21;q21) and t(14;18)(q32; q21), lead to formation of an API2-MALT1 fusion or IgH-mediated MALT1 overexpression. Various approaches have implicated these proteins in nuclear factor kappaB (NF-kappa B) signaling, but this has not been shown experimentally in human B cell...
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