Keratinocyte apoptosis by Daxx-ASK1-JNK-p38 pathway

细胞在各种细胞外刺激下发生分化。这种细胞反应需要细胞内信号通路。丝裂原活化蛋白激酶级联是决定多种细胞命运的核心信号转导途径。MAP激酶激活MAP激酶，MAP激酶又激活MAP激酶。凋亡信号调节激酶（Apoptosis signal-regulating kinase, ASK1）是一种MAP激酶，参与应激诱导的凋亡信号级联反应，激活SEK1-JNK和MKK3/MKK6-p38 MAP激酶级联反应。角化细胞中组成型活性ASK1 （ASK1-ΔN）的表达诱导了显著的形态变化和分化标志物，转谷氨酰胺酶-1、氯丙林和天花素。p21^<Cip1/WAF1>的短暂增加，DNA合成减少和细胞周期分析证实了分化。p38 MAP激酶抑制剂SB202190和SB203580可抑制分化标志物转谷氨酰胺酶-1、氯丙林和天花苷的诱导。反过来，角化细胞中神经酰胺诱导分化导致ASK1表达和活性增加。此外，正常人类皮肤在上表皮表达ASK1蛋白，暗示ASK1参与体内角质形成细胞的分化。我们提出ASK1-p38 MAP激酶级联是角质形成细胞分化的一种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.