Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation

Koji Sayama, Yasushi Hanakawa, Yuji Shirakata, Kenshi Yamasaki, Yasuhiro Sawada, Lin Sun, Kiyofumi Yamanishi, Hidenori Ichijo, Koji Hashimoto

Research output: Contribution to journalArticlepeer-review

112 Citations (Scopus)


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-AN) in keratinocytes induced significant morphological changes and differentiation markers, transglutaminase-1, loricrin, and involucrin. A transient increase in p21Cip1/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 ASKl-p38 MAP kinase cascade is a new intracellular regulator of keratinocyte differentiation.

Original languageEnglish
Pages (from-to)999-1004
Number of pages6
JournalJournal of Biological Chemistry
Issue number2
Publication statusPublished - 2001 Jan 12
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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