API2-MALT1 fusion protein induces transcriptional activation of the API2 gene through NF-kappaB binding elements: evidence for a positive feed-back loop pathway resulting in unremitting NF-kappaB activation.
t(11;18)(q21;q21) is a characteristic as well as the most frequent chromosomal translocation in mucosa-associated lymphoid tissue (MALT) type lymphoma, and this translocation results in a fusion transcript, API2-MALT1. Although API2-MALT1 has been shown to enforce activation of NF-kappaB signaling, the transcriptional target genes of this fusion protein remains to be identified. Our analyses of the API2-MALT transfectants suggested that one of the target genes may be the apoptotic inhibitor API2 gene. Luciferase reporter assays with deletion and mutational constructs of the API2 promoter and electrophoretic mobility shift assays established that API2-MALT1 induces transcriptional activation of the API2 gene through two NF-kappaB binding elements. Moreover, supershift experiments indicated that these elements are recognized by the NF-kappaB p50/p65 heterodimer. Taken together, our results strongly indicated that API2-MALT1 possesses a novel mechanism of self-activation by up-regulating its own expression in t(11;18)(q21;q21)-carrying MALT lymphomas, highlighting a positive feedback-loop pathway resulting in unremitting NF-kappaB activation.
Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan. yhosokaw@aichi-cc.jp
Yoshitaka
Y
Hosokawa
Hiroko
H
Suzuki
Masao
M
Nakagawa
Tae H
TH
Lee
Masao
M
Seto
D001665:Binding Sites; D002460:Cell Line; D005246:Feedback / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D015533:Transcriptional Activation
C415943:API2-MALT1 fusion protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion