title: Transcriptional regulation of the interleukin-11 gene by oncogenic Ras.
abstract: Interleukin-11 (IL-11), which belongs to a class of IL6-type cytokines, plays an important role in inflammation, motility and invasion in cancer. The ras mutation is frequently found in human cancer, but little is known regarding the transcriptional activation of the IL-11 gene by the Ras signal pathway in tumour cells. In this study, we investigated the role of Ras in the regulation of IL-11 using two different cell model systems: mouse NIH3T3 cells over-expressing oncogenic Ras with a tet-on system and Capan-1 human pancreatic carcinoma cells harbouring a K-ras mutation. We found that IL-11 expression was up-regulated at the transcriptional level by oncogenic Ras. Activation of the AP-1 response element, located between -153 and -30 in the 5'-regulatory region of the IL-11 gene, was necessary for oncogenic Ras-induced IL-11 promoter activation. AP-1 proteins, including Fra-1 and Fra-2, were up-regulated through the Raf/MEK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways by oncogenic Ras. Knockdown of Fra-1 by siRNA in NIH3T3 or Capan-1 cells strongly attenuated oncogenic Ras-induced IL-11 expression. Additionally, inhibition of JNK, p38 and Stat3 abrogated oncogenic Ras-induced IL-11 expression. These results suggest that both the PI3K and Raf pathways are necessary for the expression of IL-11 in oncogenic Ras-mutated cells, and that JNK, p38 and Stat3 also contribute to oncogenic Ras-induced IL-11 expression.
authors.affiliation: Department of Biomedical Science and Technology, SMART Institute of Advanced Biomedical Science, Research Center for Transcription Control, Konkuk University,  Seoul 143-701, Republic of Korea.
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
authors.forename: Chan
authors.initials: C
authors.lastname: Choi
authors.forename: Hong Ghi
authors.initials: HG
authors.lastname: Lee
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics*; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology; D014158:Transcription, Genetic; D048490:raf Kinases / Q000502:physiology; D000099169:Fos-Related Antigen 1
chemical_list: D017370:Interleukin-11; D019869:Phosphatidylinositol 3-Kinases; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D048490:raf Kinases; D000099169:Fos-Related Antigen 1