Keratinocyte apoptosis by Daxx-ASK1-JNK-p38 pathway

细胞在不同的细胞外刺激下分化。这种细胞反应需要细胞内的信号通路。丝裂原活化蛋白(MAP)激酶级联是决定多种细胞命运的核心信号转导途径。MAPK激活MAPK，进而激活MAPK。细胞凋亡信号调节蛋白激酶(ASK1)参与应激诱导的细胞凋亡信号通路，激活SEK1-JNK和MKK3/MKK6-p38通路。在角质形成细胞中表达具有组成活性的ASK1(ASK1-ΔN)诱导了显著的形态变化和分化标志物转谷氨酰胺酶-1、氯化蛋白和总蛋白。P21^&lt；Cip1/WAF1&gt；一过性增加，DNA合成减少，细胞周期分析证实了分化。P38 MAP激酶抑制剂SB202190和SB203580可阻断分化标记物转谷氨酰胺酶-1、氯化三氯乙酸甘油酯和三氯半胱氨酸的诱导作用。反过来，神经酰胺诱导角质形成细胞分化导致ASK1表达和活性增加。此外，正常人皮肤在上表皮表达ASK1蛋白，提示ASK1参与了体内角质形成细胞的分化。我们认为ASK1-p38 MAP Kinase级联是角质形成细胞分化的新的细胞内调节因子。

Cells differentiate in response to various extracellular stimuli. This cellular response requires intracellular signaling pathways. The mitogen-activated protein (MAP) kinase cascade is a core signal transduction pathway that determines the fate of many kinds of cell. MAP kinase kinase kinase activates MAP kinase kinase, which in turn activates MAP kinase. Apoptosis signal-regulating kinase (ASK1) was identified as a MAP kinase kinase kinase involved in the stress-induced apoptosis-signaling cascade that activates the SEK1-JNK and MKK3/MKK6-p38 MAP kinase cascades. Expression of the constitutively active form of ASK1 (ASK1-ΔN) in keratinocytes induced significant morphological changes and differentiation markers, transglutaminase-1, loricrin, and involucrin. A transient increase in p21^<Cip1/WAF1>, reduced DNA synthesis and cell cycle analysis verified the differentiation. p38 MAP kinase inhibitors, SB202190 and SB203580, abolished the induction of differentiation markers, transglutaminase-1, loricrin and involucrin. In turn, the induction of differentiation with ceramide in keratinocytes caused an increase in ASK1 expression and activity. Furthermore, normal human skin expresses ASK1 protein in the upper epidermis, implicating ASK1 in in vivo keratinocyte differentiation.We propose that the ASK1-p38 MAP Kinase cascade is a new intracellular regulator of keratinocyte differentiation.