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首页> 外文期刊>Journal of Cellular Physiology >The xenoestrogens biphenol‐A and nonylphenol differentially regulate metalloprotease‐mediated shedding of EGFR ligands
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The xenoestrogens biphenol‐A and nonylphenol differentially regulate metalloprotease‐mediated shedding of EGFR ligands

机译：的xenoestrogens双苯酚和壬基酚不同调节metalloprotease介导脱落的表皮生长因子受体配体

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The xenoestrogens bisphenol‐A (BPA) and nonylphenol (NP) are endocrine disruptors used in the plastic polymer industry to manufacture different products for human use. Previous studies have suggested a role of these compounds in the shedding of signaling molecules, such as tumor necrosis factor α (TNF‐α). The aim of this work was to evaluate the effect of BPA and NP on the sheddase ADAM17 and its newly discovered regulators iRhom1 and iRhom2 in the release of EGFR‐ligands. We report that BPA and NP can stimulate the release of the ADAM17‐substrates HB‐EGF and TGF‐α. In cells lacking ADAM17 ( Adam17 ?/? mEFs) BPA‐stimulated release of HB‐EGF, but not TGF‐α, was strongly reduced, whereas NP‐stimulated shedding of HB‐EGF and TGF‐α was completely abolished. Inactivation of both ADAM17 and the related ADAM10 ( Adam10/17 ?/? mEFs) completely prevented the release of these substrates. In the absence of iRhom1, BPA‐ or NP‐stimulated release of HB‐EGF or TGF‐α was comparable to wild‐type control mEFs, conversely the BPA‐induced release of HB‐EGF was abolished in iRhom2 ?/? mEFs. The defect in shedding of HB‐EGF in iRhom2 ?/? mEF cells could be rescued by overexpressing iRhom2. Interestingly, the NP‐stimulated release of HB‐EGF was not affected by the absence of iRhom2, suggesting that NP could potentially activate both ADAM10 and ADAM17. We tested this hypothesis using betacellulin (BTC), an EGFR‐ligand that is a substrate for ADAM10. We found that NP, but not BPA stimulated the release of BTC in Adam17 ?/? , iRhom2 ?/? , or iRhom1/2 ?/? , but not in Adam10/17 ?/? cells. Taken together, our results suggest that BPA and NP stimulate the release of EGFR‐ligands by differentially activating ADAM17 or ADAM10. The identification of specific effects of these endocrine disruptors on ADAM10 and ADAM17 will help to provide a better understanding of their roles in cell signaling and proinflammatory processes, and provide new potential targets for treatment of reproductive or inflammatory diseases such as asthma or breast cancer that are promoted by xenoestrogens.
机译：的xenoestrogens双酚A (BPA)和应承担的壬基酚(NP)内分泌干扰物中使用塑料聚合物工业生产不同的产品供人类使用。研究表明这些化合物的作用脱落的信号分子,如肿瘤坏死因子α(肿瘤坏死因子α应承担的)。工作是评估BPA和NP的效果的sheddase ADAM17及其新发现监管者iRhom1和iRhom2释放表皮生长因子受体的配体。刺激的释放ADAM17基质HB EGF和转化生长因子α。Adam17 ? / ?HB EGF应承担的,但不是TGF高α强烈降低,而NP量刺激HB EGF和脱落TGFα应承担完全废除。ADAM17和相关ADAM10 (Adam10/17/ ?这些基质。或者NP刺激释放HB EGF或者TGF应承担的α地理与野生型控制mef,相反BPA检测诱导释放HB EGF被废除在iRhom2 ? / ?HB EGF应承担iRhom2 ? / ?由overexpressing iRhom2。NP量刺激释放HB EGF没有影响缺乏iRhom2,表明NP可能会激活ADAM10和ADAM17。betacellulin (BTC),一个一个表皮生长因子受体配体ADAM10生长的基质。BPA刺激释放BTC Adam17 ? / ?iRhom2 ? / ?Adam10/17 ? / ?表明BPA和NP刺激的释放不同激活ADAM17 EGFR检测配体或ADAM10。这些ADAM10和内分泌干扰物ADAM17将有助于提供一个更好的理解他们的角色在细胞信号和促炎的过程,并提供新的生殖的潜在的治疗目标或炎性疾病如哮喘或乳房癌症xenoestrogens提拔的。

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