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Vol. 19, Issue 11, 4717-4729, November 2008

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Antagonistic Regulation of Cell-Matrix Adhesion by FosB and FosB/2FosB Encoded by Alternatively Spliced Forms of fosB Transcripts

Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan

Submitted August 9, 2007; Revised August 8, 2008; Accepted August 20, 2008
Monitoring Editor: William P. Tansey

Among fos family genes encoding components of activator protein-1 complex, only the fosB gene produces two forms of mature transcripts, namely fosB and fosB mRNAs, by alternative splicing of an exonic intron. The former encodes full-length FosB. The latter encodes FosB and 2FosB by alternative translation initiation, and both of these lack the C-terminal transactivation domain of FosB. We established two mutant mouse embryonic stem (ES) cell lines carrying homozygous fosB-null alleles and fosB^d alleles, the latter exclusively encoding FosB/2FosB. Comparison of their gene expression profiles with that of the wild type revealed that more than 200 genes were up-regulated, whereas 19 genes were down-regulated in a FosB/2FosB-dependent manner. We furthermore found that mRNAs for basement membrane proteins were significantly up-regulated in fosB^d/d but not fosB-null mutant cells, whereas genes involved in the TGF-β1 signaling pathway were up-regulated in both mutants. Cell-matrix adhesion was remarkably augmented in fosB^d/d ES cells and to some extent in fosB-null cells. By analyzing ES cell lines carrying homozygous fosB^FN alleles, which exclusively encode FosB, we confirmed that FosB negatively regulates cell-matrix adhesion and the TGF-β1 signaling pathway. We thus concluded that FosB and FosB/2FosB use this pathway to antagonistically regulate cell matrix adhesion.

Address correspondence to: Yusaku Nakabeppu (yusaku{at}bioreg.kyushu-u.ac.jp)