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當然有些東西不是很準 高手幫忙給我修改下
Abstract
We have previously shown that keratinocyte-specific deletion of Smad4, a TGFp/Activin/BMP signaling mediator, results in a progressive alopecia. To further assess the molecular mechanisms of Smad4 loss-mediated alopecia, we examined expression levels of key molecules associated with hair follicle differentiation in Smad4-deleted skin. Among them, Desmoglein 4 (Dsg4) was down regulated in Smad4-deleted skin prior to the onset of hair follicle abnormalities with gradual depletion coinciding with hair follicle degeneration. Chromatin immunoprecipitation (ChIP) assay showed that Smad4, together with the BMP mediators Smadl and SmadS, but not the TGFp/Activin mediators Smad2 or Smad3, bound to the Smad Binding Element (SBE) of the Dsg4 promoter. A Dsg4 reporter assay revealed that Smad4 was required for the maximal transactivation of Dsg4 in cooperation with Smadl and SmadS. Mutating the SBE of the Dsg4 promoter abrogated Smad4 transactivation of Dsg4. Furthermore, BMP ligands, but not ligands of TGFp and Activin, induced endogenous Dsg4 expression. Our data demonstrate that in the presence of Smad4, BMP signaling participated in transcriptional regulation of Dsg4. Thus, Smad4 loss-associated Dsg4 depletion contributed, at least in part, to hair follicles degeneration in Smad4 deficient skin.
摘要
我們先前的研究顯示特異性角質細胞缺失Smad4,一種TGFp /活化素/ BMP信令調停,導致進一步的脫發。 為了進一步評估Smad4缺失的分子脫發機制,我們研究與缺失Smad4的皮膚毛囊分化有關的重要分子的表達水平。 其中,在缺失Smad4皮膚中橋粒芯蛋白4(Dsg4)先于毛發逐漸的消耗和退化而畸形之前下降。染色質免疫沉淀(ChIP)實驗表明,Smad4與同骨形態發生蛋白Smadl及SMADs, 促使Dsg4啟動子蛋白元素(SBE法)的的結合。而不是TGFp /激活蛋白Smad2或Smad3,一個關于Dsg4的報告分析發現,Smad4在Dsg4與Smadl和SMADs的最大式激活中是必需的。變異的Dsg4啟動子阻止Smad4的Dsg4反式激活。 此外,bmp配體誘導內源性Dsg4的表達,而不是TGFp和Activin配體。我們的數據表明,在Smad4的存在下,BMP信號參與Dsg4調控的轉錄。 因此,至少在部分Smad4變性的皮膚毛囊中,Smad4缺失相關Dsg4的功能。 |
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