Dai Xiuju, Sayama Koji, Shirakata Yuji, Hanakawa Yasushi, Yamasaki Kenshi, Tokumaru Sho, Yang Lujun, Wang Xiaoling, Hirakawa Satoshi, Tohyama Mikiko, Yamauchi Toshimasa, Takashi Kadowaki, Kagechika Hiroyuki, Hashimoto Koji
Department of Dermatology, Ehime University School of Medicine, Ehime, Japan.
J Invest Dermatol. 2007 Jul;127(7):1728-35. doi: 10.1038/sj.jid.5700758. Epub 2007 Mar 1.
Signal transducers and activators of transcription (STATs) are critical to growth factor-mediated intracellular signal transduction. We observed the rapid expression and activation of STAT5a during keratinocyte differentiation induced by suspension culture. STAT5a expression preceded that of involucrin, an important molecule in the terminal differentiation of keratinocytes. To determine whether STAT5a regulated involucrin expression, we expressed a dominant-negative (dn) STAT5a that blocks the dimerization of STAT5 and inhibits its nuclear translocation. We found that dn-STAT5a inhibited involucrin expression in keratinocytes. Given that STAT5 regulates adipogenesis via activating the peroxisome proliferator-activated receptor (PPAR) gamma signal, we hypothesized that STAT5a regulated involucrin expression in the same manner. To test this hypothesis, we examined the expression and transactivation of PPARgamma in a suspension culture of keratinocytes. Suspension culture induced PPARgamma expression and triggered PPARgamma transactivation rapidly and dn-STAT5a downregulated this induction and suppressed PPARgamma transactivation. Furthermore, preincubation with the PPARgamma/retinoid X-receptor inhibitor HX-531 or the introduction of a dn-PPARgamma prevented the activation of involucrin promoter and inhibited its induction. This report provides early evidence of a major role for STAT5a in the differentiation of keratinocytes, where it contributes to involucrin expression by activating the PPARgamma signal.
信号转导子和转录激活子（STATs）对于生长因子介导的细胞内信号转导至关重要。我们观察到在悬浮培养诱导的角质形成细胞分化过程中，STAT5a迅速表达并被激活。STAT5a的表达先于兜甲蛋白，兜甲蛋白是角质形成细胞终末分化中的一个重要分子。为了确定STAT5a是否调节兜甲蛋白的表达，我们表达了一种显性负性（dn）STAT5a，它可阻断STAT5的二聚化并抑制其核转位。我们发现dn-STAT5a抑制角质形成细胞中兜甲蛋白的表达。鉴于STAT5通过激活过氧化物酶体增殖物激活受体（PPAR）γ信号来调节脂肪生成，我们推测STAT5a以相同方式调节兜甲蛋白的表达。为了验证这一假设，我们检测了角质形成细胞悬浮培养中PPARγ的表达和反式激活。悬浮培养迅速诱导PPARγ表达并触发PPARγ反式激活，而dn-STAT5a下调这种诱导并抑制PPARγ反式激活。此外，用PPARγ/视黄酸X受体抑制剂HX-531预孵育或导入dn-PPARγ可阻止兜甲蛋白启动子的激活并抑制其诱导。本报告提供了早期证据，表明STAT5a在角质形成细胞分化中起主要作用，它通过激活PPARγ信号促进兜甲蛋白的表达。
