Soluble form of heparin-binding EGF-like growth factor contributes to retinoic acid-induced epidermal hyperplasia
Soluble form of heparin-binding EGF-like growth factor contributes to retinoic acid-induced epidermal hyperplasia
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DOI：
10.1247/csf.30.35
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发表时间：
2005-12-01
影响因子：
1.5
通讯作者：
Mekada, E
中科院分区：
文献类型：
--
作者：
Kimura, R;Iwamoto, R;Mekada, E
肝素结合表皮生长因子样生长因子（HB-EGF），EGF家族的成员，被认为是角质形成细胞功能的重要。HB-EGF首先以膜锚定形式合成，其可溶形式通过胞外域脱落释放。在这里，我们调查的作用，HB-EGF诱导的表皮增生全性状维甲酸（tRA）治疗。HB-EGF通常在正常成年小鼠的表皮中以非常低的水平表达，但是局部tRA治疗导致表皮增生，伴随着在基底上层中HB-EGF表达的强烈诱导。与野生型HB-EGF敲入小鼠（HBlox/lox）相比，在角质形成细胞特异性HB-EGF缺失小鼠（K5-HDdel/del）和表达HB-EGF不可切割突变形式的敲入小鼠（HBuc/uc）中，tRA诱导的表皮增生减少。在ErbB酪氨酸激酶受体中，EGF受体（EGFR）和ErbB 2被选择性地激活，而这些ErbB受体的激活在HB-EGF裸小鼠的皮肤中被显著降低。这些结果表明，HB-EGF的表达及其可溶性形式的产生，随后EGFR和ErbB 2的活化，是tRA诱导的表皮增生的关键过程。
Heparin-binding EGF-like growth factor (HB-EGF), a member of the EGF-family, is thought to be important for keratinocyte functions. HB-EGF is first synthesized as a membrane-anchored form, and its soluble form is released by ectodomain shedding. Here we investigate the role of HB-EGF in epidermal hyperplasia induced by all-traits retinoic acid (tRA) treatment. HB-EGF is normally expressed in epidermis of normal adult mice at very low levels, but topical tRA treatment results in epidermal hyperplasia, concomitant with the strong induction of HB-EGF expression in the suprabasal layer. tRA-induced epidermal hyperplasia was reduced both in the keratinocyte-specific HB-EGF null mice (K5-HDdel/del) and knock-in mice expressing the uncleavable mutant form of HB-EGF (HBuc/uc), as compared with wild-type HB-EGF knock-in mice (HBlox/lox). Among ErbB tyrosine kinase receptors, EGF receptor (EGFR) and ErbB2 were selectively activated by tRA treatment in skin from wild-type mice, while the activation of these ErbB receptors was significantly reduced in the skin of HB-EGF null mice. These results indicate that expression of HB-EGF and generation of its soluble form, followed by activation of EGFR and ErbB2, are pivotal processes in tRA-induced epidermal hyperplasia.