Sayama Koji, Hanakawa Yasushi, Nagai Hiroshi, Shirakata Yuji, Dai Xiuju, Hirakawa Satoshi, Tokumaru Sho, Tohyama Mikiko, Yang Lujun, Sato Shintaro, Shizuo Akira, Hashimoto Koji
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295.
J Biol Chem. 2006 Aug 4;281(31):22013-22020. doi: 10.1074/jbc.M601065200. Epub 2006 Jun 5.
Transforming growth factor-beta-activated kinase 1 (TAK1) is a member of the mitogen-activated protein (MAP) kinase family and is an upstream signaling molecule of nuclear factor-kappaB (NF-kappaB). Given that NF-kappaB regulates keratinocyte differentiation and apoptosis, TAK1 may be essential for epidermal functions. To test this, we generated keratinocyte-specific TAK1-deficient mice from Map3k7(flox/flox) mice and K5-Cre mice. The keratinocyte-specific TAK1-deficient mice were macroscopically indistinguishable from their littermates until postnatal day 2 or 3, when the skin started to roughen and wrinkle. This phenotype progressed, and the mice died by postnatal day 7. Histological analysis showed thickening of the epidermis with foci of keratinocyte apoptosis and intra-epidermal micro-abscesses. Immunohistochemical analysis showed that the suprabasal keratinocytes of the TAK1-deficient epidermis expressed keratin 5 and keratin 14, which are normally confined to the basal layer. The expression of keratin 1, keratin 10, and loricrin, which are markers for the suprabasal and late phase differentiation of the epidermis, was absent from the TAK1-deficient epidermis. Furthermore, the TAK1-deficient epidermis expressed keratin 16 and had an increased number of Ki67-positive cells. These data indicate that TAK1 deficiency in keratinocytes results in abnormal differentiation, increased proliferation, and apoptosis in the epidermis. However, the keratinocytes from the TAK1-deficient epidermis induced keratin 1 in suspension culture, indicating that the TAK1-deficient keratinocytes retain the ability to differentiate. Moreover, the removal of TAK1 from cultured keratinocytes of Map3k7(flox/flox) mice resulted in apoptosis, indicating that TAK1 is essential for preventing apoptosis. In conclusion, TAK1 is essential in the regulation of keratinocyte growth, differentiation, and apoptosis.
转化生长因子-β 激活激酶 1（TAK1）是丝裂原活化蛋白（MAP）激酶家族的成员，也是核因子-κB（NF-κB）的上游信号分子。鉴于 NF-κB 调节角质形成细胞的分化和凋亡，TAK1 可能对表皮功能至关重要。为了验证这一点，我们从 Map3k7(flox/flox) 小鼠和 K5-Cre 小鼠中培育出了角质形成细胞特异性 TAK1 缺陷小鼠。在出生后第 2 天或第 3 天之前，角质形成细胞特异性 TAK1 缺陷小鼠在宏观上与它们的同窝小鼠没有区别，之后皮肤开始变得粗糙和起皱。这种表型不断发展，小鼠在出生后第 7 天死亡。组织学分析显示表皮增厚，伴有角质形成细胞凋亡灶和表皮内微脓肿。免疫组织化学分析表明，TAK1 缺陷表皮的基底上层角质形成细胞表达角蛋白 5 和角蛋白 14，而这些蛋白通常局限于基底层。TAK1 缺陷表皮中不存在作为表皮基底上层和晚期分化标志物的角蛋白 1、角蛋白 10 和兜甲蛋白的表达。此外，TAK1 缺陷表皮表达角蛋白 16，且 Ki67 阳性细胞数量增加。这些数据表明，角质形成细胞中 TAK1 的缺陷导致表皮异常分化、增殖增加和凋亡。然而，TAK1 缺陷表皮的角质形成细胞在悬浮培养中诱导角蛋白 1 的表达，这表明 TAK1 缺陷的角质形成细胞保留了分化能力。此外，从 Map3k7(flox/flox) 小鼠的培养角质形成细胞中去除 TAK1 会导致凋亡，这表明 TAK1 对于预防凋亡至关重要。总之，TAK1 在调节角质形成细胞的生长、分化和凋亡中至关重要。
