Antagonistic Regulation of Cell-Matrix Adhesion by FosB and ΔFosB/Δ2ΔFosB Encoded by Alternatively Spliced Forms of fosB Transcripts
Antagonistic Regulation of Cell-Matrix Adhesion by FosB and ΔFosB/Δ2ΔFosB Encoded by Alternatively Spliced Forms of fosB Transcripts
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DOI：
10.1091/mbc.e07-08-0768
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发表时间：
2008-11-01
影响因子：
3.3
通讯作者：
Nakabeppu, Yusaku
中科院分区：
文献类型：
--
作者：
Ohnishi, Yoshinori N.;Sakumi, Kunihiko;Nakabeppu, Yusaku
在编码激活蛋白-1复合物组分的fos家族基因中，只有fosB基因通过外显子内含子的选择性剪接产生两种形式的成熟转录物，即fosB和Delta fosB mrna。前者编码全长FosB。后者通过替代翻译起始编码Delta FosB和Delta 2 Delta FosB，两者都缺乏FosB的c端反激活结构域。我们建立了两个携带纯合子fob -null等位基因和fosB(d)等位基因的突变小鼠胚胎干（ES）细胞系，后者专门编码Delta fosB /Delta 2 Delta fosB。与野生型的基因表达谱比较发现，在Delta FosB/Delta 2依赖Delta FosB的情况下，有200多个基因表达上调，19个基因表达下调。我们进一步发现，基底膜蛋白mrna在fosB（d/d）突变细胞中显著上调，而在fosB-null突变细胞中则没有上调，而tgf - β 1信号通路相关基因在两种突变细胞中均上调。在fosB(d/d) ES细胞中，细胞-基质黏附明显增强，在无fosB细胞中也有一定程度的增强。通过分析携带纯合子fosB（FN）等位基因的ES细胞系，我们证实fosB负调控细胞基质粘附和tgf - β 1信号通路。因此，我们得出结论，FosB和δ FosB/ δ 2 δ FosB利用这一途径拮抗调节细胞基质粘附。
Among fos family genes encoding components of activator protein-1 complex, only the fosB gene produces two forms of mature transcripts, namely fosB and Delta fosB mRNAs, by alternative splicing of an exonic intron. The former encodes full-length FosB. The latter encodes Delta FosB and Delta 2 Delta FosB 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 Delta FosB/Delta 2 Delta FosB. 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 Delta FosB/Delta 2 Delta FosB-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-beta 1 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-beta 1 signaling pathway. We thus concluded that FosB and Delta FosB/Delta 2 Delta FosB use this pathway to antagonistically regulate cell matrix adhesion.