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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Akanuma, Masao Hayakawa, Yoku Hirata, Yoshihiro Kinoshita, Hiroto Nakata, Wachiko Sakamoto, Kei Takeda, Kohsuke Takahashi, Ryota Maeda, Shin Koike, Kazuhiko Ichijo, Hidenori Tada, Motohisa Nakagawa, Hayato Tateishi, Keisuke Yoshida, Haruhiko Omata, Masao Hikiba, Yohko |
| Description | Author Affiliation: Hayakawa Y ( Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan.); |
| Abstract | Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and are highly active in many types of human cancers. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK involved in apoptosis, inflammation, and carcinogenesis. This study investigated the role of ASK1 in the development of gastric cancer. In human gastric cancer specimens, we observed increased ASK1 expression, compared to nontumor epithelium. Using a chemically induced murine gastric tumorigenesis model, we observed increased tumor ASK1 expression, and ASK1 knockout mice had both fewer and smaller tumors than wild-type (WT) mice. ASK1 siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced cyclin D1 expression in gastric cancer cells, whereas these effects were uncommon in other cancer cells. ASK1 overexpression induced the transcription of cyclin D1, through AP-1 activation, and ASK1 levels were regulated by cyclin D1, via the Rb-E2F pathway. Exogenous ASK1 induced cyclin D1 expression, followed by elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 2 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Cyclin D1 Metabolism Gene Expression Regulation, Neoplastic MAP Kinase Kinase Kinase 5 Stomach Neoplasms Animals Cell Cycle Cell Line, Tumor Disease Models, Animal E2F Transcription Factors Mice Mice, Inbred C57BL Mice, Transgenic Signal Transduction Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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