p63/p51-induced Onset of Keratinocyte Differentiation via the c-Jun N-terminal Kinase Pathway Is Counteracted by Keratinocyte Growth Factor
p63/p51-induced Onset of Keratinocyte Differentiation via the c-Jun N-terminal Kinase Pathway Is Counteracted by Keratinocyte Growth Factor
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DOI：
10.1074/jbc.m804101200
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发表时间：
2008-12-05
影响因子：
4.8
通讯作者：
Aiba, Setsuya
中科院分区：
文献类型：
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作者：
Ogawa, Eisaku;Okuyama, Ryuhei;Aiba, Setsuya
p63/p51是肿瘤抑制蛋白p53的同源物，主要表达于上皮组织，包括表皮。p63与p53类似地影响细胞死亡，并且在上皮组织的发育和上皮干细胞的维持中也起重要作用。由于p63如何调节上皮细胞分化仍不清楚，我们通过使用角质形成细胞培养系统检查了p63在角质形成细胞分化中的功能。Delta Np 63 α（Delta Np 51 B）是一种在基底角质形成细胞中特异性表达的p63亚型，可抑制特定晚期蛋白质（如聚丝蛋白和兜甲蛋白）的分化。相反，Delta Np 63 α通过c-Jun N-末端激酶（JNK）/AP-1激活诱导角蛋白1（K1），其在分化开始时表达。然而，p63并没有诱导K1在体内基底层的表达，虽然基底角质形成细胞有高水平的p63。这种差异被解释为抑制K1表达的真皮分泌的角质细胞生长因子。这种抑制通过细胞外信号相关激酶（ERK）信号传导发生，并抵消了p63介导的K1诱导。因此，p63和角质形成细胞生长因子之间的精确平衡通过JNK和ERK信号传导介导上皮细胞分化的开始。这些数据可能为包括银屑病在内的皮肤病的病理特征提供机制解释。
p63/p51, a homolog of the tumor suppressor protein p53, is chiefly expressed in epithelial tissues, including the epidermis. p63 affects cell death similar to p53, and also plays important roles in the development of epithelial tissues and the maintenance of epithelial stem cells. Because it remains unclear how p63 regulates epithelial cell differentiation, we examined the function(s) of p63 in keratinocyte differentiation through the use of a keratinocyte culture system. Delta Np63 alpha(Delta Np51B), a p63 isoform specifically expressed in basal keratinocytes, suppressed the differentiation of specific late-stage proteins, such as filaggrin and loricrin. In contrast, Delta Np63 alpha induced keratin 1 (K1), which is expressed at the start of differentiation, via c-Jun N-terminal kinase (JNK)/AP-1 activation. However, p63 did not induce K1 expression in the basal layer in vivo, although basal keratinocytes had high levels of p63. This discrepancy was explained by the suppression of K1 expression by dermis-secreted keratinocyte growth factor. This suppression occurred via extracellular signal-related kinase (ERK) signaling, and counteracted the p63-mediated induction of K1. Thus, a precise balance between p63 and keratinocyte growth factor mediates the onset of epithelial cell differentiation, through JNK and ERK signaling. These data may provide mechanistic explanations for the pathological features of skin diseases, including psoriasis.