TY  - GEN
A1  - Ruffell, Daniela A.
AV  - public
Y1  - 2007///
TI  - In Vivo Studies on the Transcriptional and Posttranslational Regulation of the CCAAT/Enhancer Binding Protein Beta
ID  - heidok7260
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/7260/
N2  - The transcription factor C/EBPbeta gene has CREB responsive elements (CRE) in its promoter, and its transcription is regulated by CREB during adipogenesis. We have generated a mouse line with a deletion of the CRE elements on the C/EBPbeta promoter and stusied the role of these elements in macrophages. We show that the CREs are important for the induction of C/EBPbeta expression following treatment of the macrophages with IFNgamma/LPS. Moreover, we found two novel targets for C/EBPbeta transcription in macrophages, that are macrophage scavenger receptor 1 (Msr1) and interleukin 13 receptor alpha1 (IL13a1). We also show that the well-known regulation of the arginase 1 gene by C/EBPbeta is dependent on the ability of CREB to upregulate C/EBPbeta. FACS analyses on our bone marrow-derived macrophage population, showed that the cells are Mac1(+), F4/80(+) and Gr1(+), typical markers of Natural Suppressor macrophages. Taken together, the C/EBPbeta target genes found in the macrophage and the cell surface markers, suggest an immunosuppressive phenotype. we propose a novel role for C/EBPbeta in mediating the molecular switch fron inflammatory to immunosuppressive macrophages. In a separate project, we study the role of the Thr188 and Ser176, Ser180 and Ser184 phosphorylation sites, which are located in the regulatory domain of the C/EBPbeta protein. Thr188 is a known MAPK phosphorylation site, whereas the three serines, whether all or some, were recently shown to be targets for GSK3beta phosphorylation. We created two mouse lines in which either Thr188, or the three serines were mutated to alanines. We analyzed the expression of the mutant C/EBPbeta in various tissues, as well as the expression of C/EBPbeta target genes in primary macrophages from both the mouse lines. We found that the three serines have a role in modulating C/EBPbeta's autoregulatory loop as well as in reducing the transcription factor's transactivational activity. Moreover, based on the migration pattern of the mutant C/EBPbeta proteins, we propose a modl suggesting cooperativity between the MAPK and GSK3beta phosphorylation sites. We conclude that the phosphorylation sites in question are implicated, whether directly or indirectly, in the modulation of the transcription factor's activity.
KW  - C/EBPbeta 
KW  -  transcription 
KW  -  phosphorylation 
KW  -  macrophages
ER  -