Mechanism and repertoire of ASC-mediated gene expression

フォーマット:

論文

責任表示:

Hasegawa, Mizuho ; Imamura, Ryu ; Motani, Kou ; Nishiuchi, Takumi ; Matsumoto, Norihiko ; Kinoshita, Takeshi ; Suda, Takashi

言語:

英語

出版情報:

American Association of Immunologists, 2009-06-15

著者名:

Hasegawa, Mizuho

Imamura, Ryu

Motani, Kou

Nishiuchi, Takumi

Matsumoto, Norihiko

Kinoshita, Takeshi

Suda, Takashi

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掲載情報:

Journal of immunology

ISSN:

0022-1767      

巻:

182

通号:

12

開始ページ:

7655

終了ページ:

7662

バージョン:

author

概要:

金沢大学がん研究所<br />Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an adaptor molecule that mediates inflammatory and apoptotic signals. Although the role of ASC in caspase-1-mediated IL-1beta and … IL-18 maturation is well known, ASC also induces NF-kappaB activation and cytokine gene expression in human cells. In this study, we investigated the molecular mechanism and repertoire of ASC-induced gene expression in human cells. We found that the specific activation of ASC induced AP-1 activity, which was required for optimal IL8 promoter activity. ASC activation also induced STAT3-, but not STAT1-, IFN-stimulated gene factor 3- or NF-AT-dependent reporter gene expression. The ASC-mediated AP-1 activation was NF-kappaB-independent and primarily cell-autonomous response, whereas the STAT3 activation required NF-kappaB activation and was mediated by a factor that can act in a paracrine manner. ASC-mediated AP-1 activation was inhibited by chemical or protein inhibitors for caspase-8, caspase-8-targeting small-interfering RNA, and p38 and JNK inhibitors, but not by a caspase-1 inhibitor, caspase-9 or Fas-associated death domain protein (FADD) dominant-negative mutants, FADD- or RICK-targeting small-interfering RNAs, or a MEK inhibitor, indicating that the ASC-induced AP-1 activation is mediated by caspase-8, p38, and JNK, but does not require caspase-1, caspase-9, FADD, RICK, or ERK. DNA microarray analyses identified 75 genes that were induced by ASC activation. A large proportion of them was related to transcription (23%), inflammation (21%), or cell death (16%), indicating that ASC is a potent inducer of inflammatory and cell death-related genes. This is the first report of ASC-mediated AP-1 activation and the repertoire of genes induced downstream of ASC activation. 続きを見る

URL:

http://hdl.handle.net/2297/18477