FUNCTIONAR ROFE OF C-FOS IN DIFFERENTIATION AND PROLIFERATION OF MATURE B CELLS

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c-Fos Induces Apoptosis in Germinal Center B CellsWe examined a role of c-Fos in differentiation of mature B cells into IgG producing cells using transgenic mice carrying the c-fos gene under the control of the IFN-a/b-inducible Mx promoter (Mx-c-fos) or the constitutive H-2^b promoter (H2-c-fos). Splenic B cells from Mx-c-fos mice were cultured with LPS and rlL-4, and IgG1^+ B cells were developed in the culture after d 3. When IEN-a/b was added in the culture from d 2, development of IgG1^+ B cells was perturbed and the number of apoptotic cells increased within 24 h, suggesting that c-Fos induces apoptosis in Ig class-switching B cells. To confirm the effect of c-Fos on the B cell differentiation in vivo, H2-c-fos mice were immunized with DNP-OVA.The mice produced primary IgM but not IgG anti-DNP Ab in sera and failed to generate germinal centers in spleen. The perturbation of germinal center formation in H2-c-fos mice was rescued by mating them with transgenic mice carrying the bcl … More -2 gene with the Ig promoter. However, primary IgG1 anti-DNP Ab production was still suppressed in doubly transgenic mice, suggesting that Bcl-2 can delay time of c-Fos-induced apoptosis in Ig class-switching B cells but cannot rescue the death. Since c-Fos is induced in mature B cells reacted with Ags and clonal deletion of self-reactive B cells in germinal centers is insensitive to Bcl-2, these results suggest that c-Fos plays a causal role in clonal deletion of germinal center B cells.Prolonged Expression of c-fos Suppresses Cell Cycle Entry of Dormant Hematopoietic Stem CellsThe proto-oncogene c-fos was transiently up-regulated in primitive hematopoietic stem (Lin^-Sca-1^+) cells stimulated with stem cell factor, interleukin-3, and interleukin-6. To investigate a role of the c-fos in hematopoietic stem cells, we used bone marrow (BM) cells from transgenic mice carrying the c-fos gene under the control of the interferon-a/b inducible Mx-promoter (Mx-c-fos), and fetal liver cells from c-fos-deficient mice. Prolonged expression of the c-fos in Lin^- Sca-1^+ BM cells inhibited factor dependent colony formation and hematopoiesis on a stromal cell layer by keeping them at G0/G1 phase of the cell cycle. These Lin^- Sca-1^+ BM cells on a stromal layer entered into the cell cycle whenever exogenous c-fos was down-regulated. However, ectopic c-fos did not perturb colony formation by Lin^- Sca-1^+ BM cells after they entered the cell cycle. Furthermore, endogenous c-fos is not essential to cell cycle progression of hematopoietic stem cells since the factor dependent and the stroma dependent hematopoiesis by Lin^- Sca-1^+ fetal liver cells from c-fos-deficient mice were not impaired. These results suggest that the c-fos induced in primitive hematopoietic stem cells negatively controls cell cycle progression and maintains them in a dormant state. Less