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首页> 外文期刊>Molecular and Cellular Biology >Ectodomain Shedding of Preadipocyte Factor 1 (Pref-1) by Tumor Necrosis Factor Alpha Converting Enzyme (TACE) and Inhibition of Adipocyte Differentiation
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Ectodomain Shedding of Preadipocyte Factor 1 (Pref-1) by Tumor Necrosis Factor Alpha Converting Enzyme (TACE) and Inhibition of Adipocyte Differentiation

机译：肿瘤坏死因子α转化酶（TACE）对前脂肪细胞因子1（Pref-1）的胞外域脱落和脂肪细胞分化的抑制

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Preadipocyte factor 1 (Pref-1), an epidermal growth factor repeat containing transmembrane protein found in the preadipocytes, inhibits adipocyte differentiation in vitro and in vivo. Here, we examined the processing of membrane form of Pref-1A to release the 50-kDa soluble form that inhibits adipocyte differentiation. The ectodomain cleavage of Pref-1 is markedly enhanced by phorbol 12-myristate 13-acetate in a dose- and time-dependent manner. The basal and stimulated cleavage is inhibited by the broad metalloproteinase inhibitor GM6001, a fact that suggests that cleavage of membrane Pref-1A is dependent on a metalloproteinase. Next, we showed that release of soluble Pref-1A is inhibited by TAPI-0 and by a tissue inhibitor of metalloproteinase-3, TIMP-3, that can inhibit tumor necrosis factor alpha converting enzyme (TACE), but not by TIMP-1 or TIMP-2. On the other hand, overexpression of TACE increases Pref-1 cleavage to produce the 50-kDa soluble form. Furthermore, this cleavage was not detected in cells with TACE mutation or with TACE small interfering RNA. TACE-mediated shedding of Pref-1 ectodomain inhibits adipocyte differentiation of 3T3-L1 cells and in Pref-1-null mouse embryo fibroblasts transduced with Pref-1A. Identification of TACE as the major protease responsible for conversion of membrane-bound Pref-1 to the biologically active diffusible form provides a new insight into Pref-1 function in adipocyte differentiation.
机译：前脂肪细胞因子1（Pref-1）是一种在前脂肪细胞中发现的含有跨膜蛋白的表皮生长因子重复序列，可在体内和体外抑制脂肪细胞的分化。在这里，我们检查了Pref-1A膜形式的加工过程，以释放抑制脂肪细胞分化的50 kDa可溶性形式。佛波醇12-肉豆蔻酸酯13-乙酸酯以剂量和时间依赖性方式显着增强Pref-1的胞外域裂解。基础和刺激的切割被宽泛的金属蛋白酶抑制剂GM6001抑制，这一事实表明膜Pref-1A的切割依赖于金属蛋白酶。接下来，我们证明了可溶的Pref-1A的释放受到TAPI-0和金属蛋白酶3组织抑制剂TIMP-3的抑制，后者可以抑制肿瘤坏死因子α转化酶（TACE），但不受TIMP-1的抑制或TIMP-2。另一方面，TACE的过表达增加了Pref-1裂解，从而产生50 kDa的可溶形式。此外，在具有TACE突变或TACE小干扰RNA的细胞中未检测到这种切割。 TACE介导的Pref-1胞外域脱落可抑制3T3-L1细胞和Pref-1A转导的Pref-1空小鼠胚胎成纤维细胞中脂肪细胞的分化。将TACE鉴定为负责将膜结合的Pref-1转化为具有生物活性的可扩散形式的主要蛋白酶，从而为Pref-1在脂肪细胞分化中的功能提供了新的见识。

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