title: Influence of melanoma inhibitory activity on transforming growth factor-beta signaling in malignant melanoma.
abstract: Melanoma cells escape transforming growth factor-beta (TGFbeta)-mediated growth inhibition by expressing the Smad (mothers against decapentaplegic homolog, Drosophila) inhibitors Ski and Sno. Here, we demonstrate that melanoma inhibitory activity (MIA) influences the expression of these inhibitors. A Smad responsive reporter construct was activated after TGFbeta1 treatment in the MIA-deficient cell clones but not in the parental cell line. According to this finding, the TGFbeta target genes JunB and Id-1 showed a strong induction of expression. Additional analyses revealed that Ski and Sno, repressors of TGFbeta/SMAD signaling, are not expressed in the MIA-deficient cells but in the parental cell line HMB2 and the mock control. Further investigation showed that Ski and Sno expression might be regulated via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling cascade. Treatment of HMB2 cells with a MEK inhibitor revealed a reduction of Ski and Sno expression, which leads to the conclusion that, in our melanoma cell model, Ski and Sno expression is regulated via MAPK/ERK signaling.
authors.affiliation: Institute of Pathology, University of Regensburg Medical School, Regensburg, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Rothhammer
authors.forename: Anja-Katrin
authors.initials: AK
authors.lastname: Bosserhoff
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D051785:Smad Proteins / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D047908:Intracellular Signaling Peptides and Proteins; C090059:MIA protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C060615:SKIL protein, human; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C060614:SKI protein, human; D020928:Mitogen-Activated Protein Kinases