Tumor Necrosis Factor- Converting Enzyme/ADAM 17 Mediates MUC1 Shedding*
Tumor Necrosis Factor- Converting Enzyme/ADAM 17 Mediates MUC1 Shedding*
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发表时间：
2003
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通讯作者：
A. Thathiah;C. Blobel;D. Carson
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作者：
A. Thathiah;C. Blobel;D. Carson
MUC 1从子宫上皮细胞表面的清除是创造有利于胚胎着床的环境的先决条件。在某些物种中，mRNA水平的降低沿着代谢周转，导致整个子宫上皮细胞在接受期MUC 1丢失。在其他物种中，MUC 1仅在胚泡附着部位迅速丢失，表明蛋白酶的作用。相关研究还表明，在体外细胞培养上清液和体内体液中存在可溶形式的MUC 1。为了表征介导MUC 1释放的蛋白水解活性，在大量表达并容易脱落MUC 1的人子宫上皮细胞系（HES）中分析MUC 1的脱落。MUC 1的释放被佛波醇12-肉豆蔻酸酯13-乙酸酯刺激，并被合成肽异羟肟酸金属蛋白酶抑制剂、肿瘤坏死因子蛋白酶抑制剂（TAPI）以及基质金属蛋白酶的内源性抑制剂、金属蛋白酶的组织抑制剂（TIMP）-3显著抑制。这些特征沿着用遗传上缺乏各种亚当斯（对于去整合素和金属蛋白酶）的细胞系进行的研究，将肿瘤坏死因子转化酶（TACE）/ADAM 17鉴定为MUC 1脱落酶。此外，TACE和MUC 1在人子宫上皮细胞中的接受期表达，免疫共沉淀实验揭示了TACE和MUC 1在HES细胞中的物理相互作用。这些研究建立了MUC 1从人子宫上皮细胞系中清除的蛋白水解机制，并将TACE鉴定为MUC 1脱落酶。
MUC1 clearance from the uterine epithelial cell surface is a prerequisite for the creation of an environment conducive to embryo implantation. In some species, reduced mRNA levels along with metabolic turnover account for loss of MUC1 during the receptive phase throughout the uterine epithelium. In other species, MUC1 is rapidly lost solely at the site of blastocyst attachment, suggesting the action of a protease. Correlative studies also indicate the presence of soluble forms of MUC1 in cell culture supernatants in vitro and in bodily fluids in vivo. To characterize the proteolytic activity mediating MUC1 release, shedding of MUC1 was analyzed in a human uterine epithelial cell line (HES) that abundantly expresses and readily sheds MUC1. MUC1 release was stimulated by phorbol 12-myristate 13-acetate and was markedly inhibited by the synthetic peptide hydroxamate metalloprotease inhibitor, tumor necrosis factorprotease inhibitor (TAPI), as well as by an endogenous inhibitor of matrix metalloproteases, tissue inhibitor of metalloproteases (TIMP)-3. These characteristics along with studies conducted with cell lines genetically deficient in various ADAMs (for a disintegrin and metalloprotease) identified tumor necrosis factorconverting enzyme (TACE)/ADAM 17 as a MUC1 sheddase. Furthermore, both TACE and MUC1 were expressed in human uterine epithelia during the receptive phase, and co-immunoprecipitation experiments revealed a physical interaction between TACE and MUC1 in HES cells. These studies establish a proteolytic mechanism for MUC1 clearance from a human uterine epithelial cell line and identify TACE as a MUC1 sheddase.