title: Intracellular NF-HEV/IL-33 harbors essential roles in Ras-induced cellular transformation by contributing to cyclin D1 protein synthesis.
abstract: A member of the interleukin-1 family, interleukin-33 (NF-HEV/IL-33), is a ligand for the receptor, ST2L and stimulates the production of Th2 cytokines. Although IL-33 localizes to the nucleus and may be involved in the regulation of transcription independent of ST2L, its functions in the nucleus currently remain unclear. We herein demonstrated that the expression of IL-33 was markedly enhanced in NIH-3T3 cells transformed by an oncogenic H-Ras mutant (H-Ras (G12V)), and the induced IL-33 was mainly located in the nuclei of these cells. The enforced expression of IL-33 accelerated H-Ras (G12V)-induced transformation in NIH-3T3 cells, and this transforming activity was markedly reduced by the knockdown of IL-33 with shRNA. We subsequently analyzed several signaling molecules regulated by Ras in order to elucidate the mechanism by which IL-33 contributes to Ras (G12V)-induced transformation. We found that the knockdown of IL-33 effectively attenuated the Ras (G12V)-induced expression of cyclin D1. However, the knockdown of IL-33 failed to affect cyclin D1 mRNA expression levels, and epoxomicin, a proteasome inhibitor, did not cancel the IL-33 knockdown-induced down-regulation of its protein levels. We showed that Ras (G12V)-induced cyclin D1 protein synthesis was markedly suppressed by the knockdown of IL-33. Taken together, the results of the present study strongly suggest a novel role for IL-33 in cellular transformation.
authors.affiliation: Division of Structural Biochemistry and Medical Biochemistry, Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Division of Structural Biochemistry and Medical Biochemistry, Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tago
authors.affiliation: Graduate School of Pharmaceutical Sciences, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Funakoshi-Tago
authors.affiliation: Division of Structural Biochemistry and Medical Biochemistry, Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
authors.forename: Jitsuhiro
authors.initials: J
authors.lastname: Matsugi
authors.affiliation: Division of Structural Biochemistry and Medical Biochemistry, Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Yanagisawa
mesh_terms: D000072283:A549 Cells; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019938:Cyclin D1 / Q000096:biosynthesis*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D000067596:Interleukin-33 / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D014176:Protein Biosynthesis; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000067596:Interleukin-33; D017472:Receptors, Interleukin-1; C530318:ST2L protein, mouse; D019938:Cyclin D1; D018631:ras Proteins
keywords: Cyclin D1; Cytokine; IL-33; Protein synthesis; Ras; Transformation