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* Division of Immunology and Molecular Biology, Cancer Research Institute, and
Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan
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-1β and IL-18 maturation is well known, ASC also induces NF-
B 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-B-independent and primarily cell-autonomous response, whereas the STAT3 activation required NF-B 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.
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1 This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas (Cancer) from the Ministry of Education, Culture, Sports, Science, and Technology, the Japanese Government.
2 Current address: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
3 Address correspondence and reprint requests to Dr. Takashi Suda, Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa, 920-0934 Japan. E-mail address: sudat{at}kenroku.kanazawa-u.ac.jp
4 Abbreviations used in this paper: CARD, caspase recruitment domain; APRE, acute-phase response element; ASC, apoptosis-associated speck-like protein containing a CARD; cmk, chloromethylketone; CLARP-S, a short isoform of caspase-like apoptosis regulatory protein; FADD, Fas-associated death domain protein; fmk, fluoromethylketone; GAS, 
-activated sequence; ISRE, IFN-stimulated response element; LRR, leucine-rich repeat; MDP, muramyl dipeptide; NLR, nucleotide-binding domain and LRR-containing protein; NOD, nucleotide-binding oligomerization domain; siRNA, small-interfering RNA; TRE, 12-O-tetradecanoylphorbol-13-acetate-responsive element.
5 The online version of this article contains supplemental material.
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