title: JNK signaling promotes intestinal tumorigenesis through activation of mTOR complex 1 in Apc(Δ716) mice.
abstract: OBJECTIVE
  Signaling by the mammalian target of rapamycin complex 1 (mTORC1) has been implicated in various human cancers. mTORC1 signaling is activated in intestinal tumors of adenomatous polyposis coli (Apc(Δ716)) mice, a model of familial adenomatous polyposis; in these mice, the mTORC1 inhibitor RAD001 can block tumor formation. However, the precise mechanism of mTORC1 signaling in intestinal tumors is not clear. We investigated whether c-Jun-NH(2) terminal kinase (JNK) is involved in the mTORC1 activation.
  
  
  METHODS
  We investigated the effects of an inhibitor and an activator of JNK, as well as small interfering RNA against JNK, on mTORC1 in Apc(Δ716) mice and colon cancer cell lines. We also determined the role of JNK in mTORC1 signaling using in vitro kinase assays.
  
  
  RESULTS
  JNK was activated in intestinal polyps of Apc((Δ716) mice); the JNK inhibitor SP600125 significantly suppressed tumor formation. In colorectal cancer cell lines, the JNK activator anisomycin activated mTORC1, whereas SP600125 or small interfering RNAs against JNK suppressed signaling. Importantly, JNK stimulated the mTORC1 kinase activity in vitro, through direct phosphorylation of Raptor at serine 863.
  
  
  CONCLUSIONS
  JNK is required for activation of mTORC1 in intestinal tumor cells. JNK inhibitors might be developed as therapeutics or to prevent development of intestinal tumors.
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-Cho, Sakyo-Ku, Kyoto, Japan.
authors.forename: Teruaki
authors.initials: T
authors.lastname: Fujishita
authors.forename: Masahiro
authors.initials: M
authors.lastname: Aoki
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D009374:Neoplasms, Experimental; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; D012334:RNA, Neoplasm; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4