2004 Fiscal Year Final Research Report Summary
Molecular analysis of malignant lymphoma-related oncogenes and its clinical application for diagnosis and treatment.
| Project/Area Number |
15591034
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Aichi Cancer Center |
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Principal Investigator |
HOSOKAWA Yoshitaka Aichi Cancer Center, Div.Molecular Medicine, Section Head, 遺伝子医療研究部, 室長 (60229193)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Malignant lymphoma / apoptosis / Chromosome translocation |
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| Research Abstract |
1)API2-MALT1. t(11;18)(q21;q21) is a characteristic chromosomal translocation in mucosa-associated lymphoid tissue(MALT) type lymphoma, and this translocation results in chimeric transcript of API2(APoptosis Inhibitor 2,also known as c-IAP2)-MALT1(Mucosa-Associated Lymphoma Translocation gene 1). To identify proteins that bind API2-MALT1 chimeric protein, we employed coimmunoprecipitation and SDS PAGE analysis, followed by liquid chromatography-electrospray ionization tandem mass spectrometry. As a result, Smac, Htra2,and TRAF2 were identified as API2-MALT1-binding proteins. Immunoprecipitation analysis demonstrated that ectopically expressed API2-MALT1 protein indeed binds to these endogeneous proteins. Furthermore, API2-MALT1 protein significantly inhibited Smac-promoted apoptosis in UV irradiated HeLa cells. These data strongly suggest that API2-MALT1 can block apoptosis, at least in part, by inhibiting Smac-mediated apoptotic pathway.
2)BCL6. The BCL-6/LAZ3 gene encodes a zinc-finge
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r transcriptional represser and is located at the breakpoint of the 3q27-associated translations that occur most frequently in non-Hodgkin's lymphomas (NHLs To examine cell responses and target genes related to the BCL-6 signaling pathway, we established Ba/F3 pro-B cells carrrying a human BCL-6 transgene that is inducible under control of the lactose operon. Using a cDNAarray hybridization technique, we found that the induced BCL-6 protein can downregulate the expressions of the genes, cyclin A2. chemokine receptor CXCR4,and insulin-like growth factor binding protein-4(IGFBP-4) in the Ba/F3 cells. Northern blot analysis established that the expressions of these genes were indeed downregulated by the induced BCL-6 protein but in a somewhat different manner. The induced BCL-6 protein also inhibited cell proliferation of Ba/F3 cells. These findings strongly suggest that three key genes, namely cyclin A2,CXCR4 and IGFBP-4 may play a role in the downstream of the BCL-6 signaling pathway during B-lymphoid differentiation. Less
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