ABSTRACT
Somatic mutations in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) have been identified in malignant melanoma and are thought to function as a driver in B-raf- or N-ras-driven tumorigenesis. To assess the role of Ppp6c in carcinogenesis, we generated skin keratinocyte-specific Ppp6c conditional knockout mice and performed two-stage skin carcinogenesis analysis. Ppp6c deficiency induced papilloma formation with 7,12-dimethylbenz (a) anthracene (DMBA) only, and development of those papillomas was significantly accelerated compared with that seen following DMBA/TPA (12-O-tetradecanoylphorbol 13-acetate) treatment of wild-type mice. NF-κB activation either by tumor necrosis factor (TNF)-α or interleukin (IL)-1ß was enhanced in Ppp6c-deficient keratinocytes. Overall, we conclude that Ppp6c deficiency predisposes mice to skin carcinogenesis initiated by DMBA. This is the first report showing that such deficiency promotes tumor formation in mice.
Subject(s)
Phosphoprotein Phosphatases/genetics , Skin Neoplasms/enzymology , 9,10-Dimethyl-1,2-benzanthracene , Animals , Carcinogenesis/metabolism , Cells, Cultured , Keratinocytes/enzymology , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Transgenic , NF-kappa B/metabolism , Phosphoprotein Phosphatases/metabolism , Signal Transduction , Skin/enzymology , Skin/pathology , Skin Neoplasms/chemically inducedABSTRACT
Porphyromonas gingivalis 381 lipopolysaccharide (LPS) definitely exhibited mitogenic activity in purified B-cells, separated from spleens of LPS-responsive C3H/HeN mice and LPS-non-responsive C3H/HeJ mice by using a magnetic cell sorting system. The mitogenic activity induced by P. gingivalis LPS was incompletely inhibited by polymyxin B. P. gingivalis LPS also induced a higher production of interleukin-6 (IL-6) in splenic B-cells of C3H/HeN mice as compared with Escherichia coli LPS. Furthermore, P. gingivalis LPS, but not E. coli LPS, induced definite IL-6 production in C3H/HeJ mice. P. gingivalis LPS increased tyrosine, serine/threonine phosphorylation of proteins with various major induced bands in splenic B-cells of both C3H/HeN and C3H/HeJ mice. Additionally, radioiodinated P. gingivalis LPS, similarly to E. coli LPS, bound to a 73-kDa protein on C3H/HeJ as well as C3H/HeN B-cells. Thus P. gingivalis LPS may activate B-cells of C3H/HeJ as well as C3H/HeN mice via the LPS-specific binding protein on the cells.
