AP-1 protein induction during monopoiesis favors C/EBP: AP-1 heterodimers over C/EBP homodimerization and stimulates FosB transcription

Journal of Leukocyte Biology

Alan D. Friedman¹  Sarah J. Wheelan  and¹  SunHwa Hong¹  Alyza M. Skaist¹ 

[1] Divisions of Pediatric Oncology and  Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

关键词: c-Jun;    c-Fos;    myeloid;    leucine zipper;   

DOI  :  10.1189/jlb.0111043

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

AP-1 proteins heterodimerize via their LZ domains to bind TGACGTCA or TGACTCA, whereas C/EBPs dimerize to bind ATTGCGCAAT. We demonstrate that intact C/EBPα also heterodimerizes with c-Jun or c-Fos to bind a hybrid DNA element, TGACGCAA, or more weakly to TGATGCAA. A 2:1 ratio of c-Jun:C/EBPα or c-Fos:C/EBPα was sufficient for preferential binding. Semiquantitative Western blot analysis indicates that the summation of c-Jun, JunB, and c-Fos levels in differentiating myeloid cells is similar to or exceeds the entirety of C/EBPα and C/EBPβ, indicating the feasibility of heterodimer formation. Induction of AP-1 proteins during monocytic differentiation favored formation of C/EBP:AP-1 heterodimers, with C/EBPα homodimers more evident during granulopoiesis. Approximately 350 human and 300 murine genes contain the TGACGCAA motif between –2 kb and +1 kb of their transcription start sites. We focused on the murine Fosb promoter, which contains a C/EBP:AP-1 cis element at –56 and –253, with the hFOSB gene containing an identical site at –253 and a 1-bp mismatch at –56. C/EBPα:AP-1 heterodimers bound either site preferentially in a gel-shift assay, C/EBPα:c-Fos ER fusion proteins induced endogenous Fosb mRNA but not in the presence of CHX, C/EBP and AP-1 proteins bound the endogenous Fosb promoter, mutation of the –56 cis element reduced reporter activity fivefold, and endogenous FosB protein was expressed preferentially during monopoiesis versus granulopoiesis. Increased expression of Jun/Fos proteins elevates C/EBP:AP-1 heterodimer formation to potentially activate novel sets of genes during monopoiesis and potentially during other biologic processes.

【 授权许可】

Unknown