title: Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer.
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.
authors.affiliation: Department of Gastroenterology, Graduate school of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Yohko
authors.initials: Y
authors.lastname: Hikiba
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Wachiko
authors.initials: W
authors.lastname: Nakata
authors.forename: Ryota
authors.initials: R
authors.lastname: Takahashi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tateishi
authors.forename: Motohisa
authors.initials: M
authors.lastname: Tada
authors.forename: Masao
authors.initials: M
authors.lastname: Akanuma
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yoshida
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Takeda
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D004195:Disease Models, Animal; D050684:E2F Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism*
chemical_list: D050684:E2F Transcription Factors; D019938:Cyclin D1; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse