Draper Bradley K, Komurasaki Toshi, Davidson Mari K, Nanney Lillian B
Department of Medicine (Dermatology), Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
J Cell Biochem. 2003 Aug 15;89(6):1126-37. doi: 10.1002/jcb.10584.
Epiregulin (EPR) is a broad specificity EGF family member that activates ErbB1 and ErbB4 homodimers and all possible heterodimeric ErbB complexes. We have previously shown that topical EPR enhances the repair of murine excisional wounds. The purpose of this study was to determine whether EPR was more effective than EGF or TGFalpha in promoting in vitro wound closure and to compare the EPR induced signal transduction pathways with those activated by EGF and TGFalpha. Normal human epidermal keratinocytes or A431 cells were scratch wounded and treated for 24 h with varying doses of EPR, EGF or TGFalpha. Five-fold lower doses of EPR were significantly better than EGF or TGFalpha in stimulating in vitro wound closure. Mitomycin-c reduced EPR induced wound closure by 59%, versus a 9% and 25% decrease in EGF and TGFalpha induced closure. The ERK/MAPK inhibitor PD-98059 decreased EPR induced wound closure by 88%. By contrast, the PLC inhibitor U-73122, only reduced the EPR induced response by 21%. Immunoblot analysis revealed that 2 nM EPR stimulated a six-fold increase in p-ERK1/2, whereas 10 nM EGF or TGFalpha stimulated only a 3- and 2.5-fold increase in p-ERK1/2. When compared with EGF or TGFalpha, EPR is a more potent and more effective inducer of in vitro wound closure due to its ability to promote significantly greater ERK/MAPK activation.
表皮调节素（EPR）是一种具有广泛特异性的表皮生长因子（EGF）家族成员，可激活ErbB1和ErbB4同二聚体以及所有可能的异二聚体ErbB复合物。我们之前已经表明，局部应用EPR可促进小鼠切除伤口的修复。本研究的目的是确定EPR在促进体外伤口闭合方面是否比EGF或TGFα更有效，并比较EPR诱导的信号转导途径与EGF和TGFα激活的信号转导途径。对正常人表皮角质形成细胞或A431细胞进行划痕损伤，并用不同剂量的EPR、EGF或TGFα处理24小时。在刺激体外伤口闭合方面，EPR的剂量低至五分之一时，效果就显著优于EGF或TGFα。丝裂霉素-c使EPR诱导的伤口闭合减少了59%，而EGF和TGFα诱导的闭合分别减少了9%和25%。ERK/MAPK抑制剂PD-98059使EPR诱导的伤口闭合减少了88%。相比之下，PLC抑制剂U-73122仅使EPR诱导的反应减少了21%。免疫印迹分析显示，2 nM EPR刺激p-ERK1/2增加了6倍，而10 nM EGF或TGFα仅刺激p-ERK1/2增加了3倍和2.5倍。与EGF或TGFα相比，EPR是一种更有效且更高效的体外伤口闭合诱导剂，因为它能够显著促进更大程度的ERK/MAPK激活。
