2000 Fiscal Year Final Research Report Summary
Keratinocyte apoptosis by Daxx-ASK1-JNK-p38 pathway
| Project/Area Number |
11670834
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Dermatology
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| Research Institution | Ehime University |
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Principal Investigator |
SAYAMA Koji Ehime Univ.Dept.of Dermatology, Assistant Processor, 医学部・附属病院, 講師 (80187286)
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| Co-Investigator(Kenkyū-buntansha) |
SHIRAKATA Yuji Ehime Univ.Dept.of Dermatology, Instructor, 医学部, 助手 (50226320)
ICHIJO Hidenori Tokyo Medical and Dental Univ., laboratory of Cell Signaling, Professor, 歯学部, 教授 (00242206)
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| Project Period (FY) |
1999 – 2000
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| Keywords | epidermis / keratinocytes / differentiation / apoptosis / MAP kinase / ASK1 / JNK / P38 MAP kinase |
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| Research Abstract |
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.
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