Anamorsin Overexpression Leads To Dysregulation Of Lipopolysaccharide-Stimulated B Cell Proliferation Through Ras Signaling

Introduction: Anamorsin (AM, also called CIAPIN1) was originally isolated as a molecule that conferred resistance to apoptosis caused by growth factor deprivation. AM deficient (AM KO) mice die during late gestation; AM KO embryos are anemic and small compared to wild type (WT) embryos. It suggests that AM is indispensable for embryo growth and hematopoiesis. To determine which signaling pathways AM utilizes for these functions, we analyzed murine embryonic fibroblast (MEF) cells generated from E-14.5 AM KO or WT embryos. Proliferation of AM KO MEF cells was markedly retarded, and PKCθ, PKCδ, and p38MAPK were more highly phosphorylated in AM KO MEF cells. Expression of cyclinD1, the target molecule of p38MAPK, was down-regulated in AM KO MEF cells. P38MAPK inhibitor as well as PKC inhibitor restored expression of cyclinD1 and cell growth in AM KO MEF cells. These data suggested that PKCθ, PKCδ, and p38MAPK activation lead to cell cycle retardation in AM KO MEF cells. However, functions of AM still remain not fully understood. In order to elucidate functions of AM, we generated AM transgenic (Tg) mice under control of CAG promoter. Since our previous study showed AM overexpression in approximately 30% of B cell type malignant lymphoma (DLBCL and FL) cases, we focused on AM overexpressed B cells from AM Tg mice in this study.