PMID:23027619

Citation	Shin, SY, Choi, C, Lee, HG, Lim, Y and Lee, YH (2012) Transcriptional regulation of the interleukin-11 gene by oncogenic Ras. Carcinogenesis 33:2467-76
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.
Links	PubMed Online version:10.1093/carcin/bgs297
Keywords	Animals; Gene Expression Regulation; Genes, ras/physiology; HEK293 Cells; Humans; Interleukin-11/genetics; Mice; Mutation; NIH 3T3 Cells; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases/physiology; Promoter Regions, Genetic; Proto-Oncogene Proteins c-fos/physiology; Transcription Factor AP-1/physiology; Transcription, Genetic; raf Kinases/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:FOSL1		GO:2000144: positive regulation of DNA-dependent transcription, initiation	ECO:0000314:		P		Measured by luciferase activity, Figure 3C, distinctly demonstrates that FRA-1 up-regulates the transcription of IL-11 over 3 fold.	complete CACAO 7690
HUMAN:FOSL1	involved_in	GO:2000144: positive regulation of DNA-templated transcription, initiation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:JUN		GO:2000144: positive regulation of DNA-dependent transcription, initiation	ECO:0000314:		P		Measured through luciferase activity, Figure 3C clearly shows that transfection of c-Jun leads to nearly a 3 fold increase in the transcription of IL-11.	complete CACAO 7693
HUMAN:JUN	involved_in	GO:2000144: positive regulation of DNA-templated transcription, initiation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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