ABSTRACT
PU.1(+/-)Spi-B(-/-) mice exhibit reduced numbers of immature and mature B lymphocytes, which exhibit severe defects in response to BCR-mediated stimulation and poor survival. We found that expression of c-rel, a member of the Rel/NF-kappa B family, is dramatically reduced in PU.1(+/-)Spi-B(-/-) splenic B cells. Analysis of the murine c-rel promoter identified three PU.1/Spi-B binding sites critical for c-rel promoter activity. Furthermore, reintroduction of Rel protein restored wild-type B cell numbers to mice reconstituted with PU.1(+/-)Spi-B(-/-) bone marrow. These findings are the first to demonstrate that a member of the Rel/NF-kappa B family is directly regulated by Ets proteins and dissect the molecular basis for the function of two Ets factors, PU.1 and Spi-B, in promoting B lymphocyte survival.
Subject(s)
B-Lymphocytes/immunology , DNA-Binding Proteins/physiology , Proto-Oncogene Proteins c-rel/genetics , Proto-Oncogene Proteins/physiology , Trans-Activators/physiology , Transcription Factors/physiology , Animals , Binding Sites , Bone Marrow Cells/immunology , Bone Marrow Transplantation , Cell Line , Cell Survival , Cells, Cultured , DNA-Binding Proteins/genetics , Down-Regulation , Gene Expression Regulation , Mice , Mice, Knockout , Promoter Regions, Genetic , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-rel/biosynthesis , RNA, Messenger/biosynthesis , Spleen/immunology , Trans-Activators/genetics , Transcription Factors/genetics , TransfectionABSTRACT
Decreased oxygen (O2) levels activate hypoxia-inducible factor (HIF-1) to induce genes involved in glycolysis, glucose transport, erythropoiesis, and angiogenesis. Mutations in various HIF-1 subunits have contributed to our understanding of the role hypoxia plays during early embryonic development in general and the cardiovascular system in particular. We propose that HIF-1 is important for the generation, proliferation, maintenance, and differentiation of the early cardiovascular system. Understanding aberrations in these hypoxic responses is important since they contribute to serious human disease such as ischemia and tumorigenesis. In this review we will focus on the critical role of O2 in regulating cardiovascular events during early embryonic development.
