Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein.
At least three recurrent chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), involving the API2-MALT1 fusion protein, BCL10 and MALT1, have been implicated in the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma. Several lines of evidence indicated that both BCL10 and MALT1 are required for nuclear factor kappa B (NF-kappaB) activation by antigen receptor stimulation in lymphocytes, and API2-MALT1 can bypass this BCL10/MALT1 signaling pathway. Nuclear factor kappa B activation may contribute to antiapoptotic effect through NF-kappaB-mediated upregulation of apoptotic inhibitor genes. We recently demonstrated that API2-MALT1 can induce transactivation of the API2 gene through NF-kappaB activation, thus highlighting a positive feedback-loop mechanism of self-activation by upregulating its own expression in t(11;18) MALT lymphomas. We also demonstrated that API2-MALT1 possesses an antiapoptotic effect, in part, through its direct interaction with apoptotic regulators. These findings therefore led us to hypothesize that the antiapoptotic effect by API2-MALT1 may be mediated by its interaction with apoptotic regulators, on the one hand, and by NF-kappaB-mediated upregulation of apoptotic inhibitor genes on the other. We also found that BCL10 and MALT1 are shuttling between nucleus and cytoplasm, and that MALT1 can regulate the subcellular location of BCL10.
Division of Molecular Medicine, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan.
M
M
Nakagawa
M
M
Seto
Y
Y
Hosokawa
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008957:Models, Genetic; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
C415943:API2-MALT1 fusion protein, human; D015514:Oncogene Proteins, Fusion