Project description:In this study we used bioluminescent reporter mice to discover that transplantable tumors cause nuclear factor-kappa B activation in host macrophages. This effect is mostly aggravated in mouse models of malignant pleural effusion, is dependent on KRAS mutation status of tumor cells, and is delivered via secretory versican, a toll-like receptor 2 ligand. Versican, in turn activates nuclear factor-kappa B in host macrophages via the canonical inhibitor of nuclear factor-kappa B kinase beta (IKKbeta), resulting in release of myeloid-secreted interleukin-1beta in the tumor microenvironment. Silencing of versican in cancer cells or conditional deletion of IKKbeta in macrophages abrogates myeloid nuclear factor-kappa B activation as well as tumor progression.
Project description:Unique and shared cytogenetic abnormalities have been documented for marginal zone lymphomas (MZLs) arising at different sites. Recently, homozygous deletions of the chromosomal band 6q23, involving the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) gene, a negative regulator of NF-kappa B, were described in ocular adnexal MZL, suggesting a role for A20 as a tumor suppressor in this disease entity. Here, we investigated inactivation of A20 by DNA mutations or deletions in a panel of extranodal (EMZL), nodal (NMZL) and splenic (SMZL) MZLs. Inactivating mutations encoding truncated A20 proteins were identified in 6/32 (18.8%) MZLs, including 3/11 (27.3%) EMZLs, 2/9 (22.2%) NMZLs, and 1/12 (8.3%) SMZLs. Two additional unmutated non-splenic MZLs also showed mono- or biallelic A20 deletions by FISH and/or array-CGH. Thus, A20 loss by both somatic mutations and/or deletions represents a common genetic aberration across all MZL subtypes, which may contribute to lymphomagenesis by inducing constitutive NF-kappa B activation. Keywords: Genome variation profiling by SNP array 27 MZL samples. No technical replications.
Project description:The activation signaling of transcription factor nuclear factor-kB (NF-kB) plays central role for immune system. One of key kinase mediating this pathway is TAK1 in adaptive and innate immunity. However, role of TAK1 in bone marrow B cell is still unclear. To know effects of TAK1-deletion, the gene expression of Ig-lambda/kappa positive cells were analyzed in comparison of wild type with TAK1-deficient bone marrow B cells.
Project description:Bone marrow derived cells stimulated with RANKL (receptor activator of nuclear factor kappa B ligand, also known as Tumor necrosis factor ligand superfamily member 11) to generate osteoclasts.
