Negative regulation of onconstatin M signaling by suppressor of cytokine signaling (SOCS-3).
Oncostatin M (OSM) is known to inhibit the growth of melanocytes and early-stage melanomas, but this ability is lost with melanoma progression. The biological effects of OSM involve the activation of Janus kinases (Jak) and signal transducer and activator of transcription (STAT) factors. Since SOCS (suppressor of cytokine signaling) a recently described family of regulatory proteins, has been shown to act through down-regulation of Jak-STAT signaling, we investigated their putative role in the inhibition of OSM signaling in the human melanoma cell line A375. We observed that, among the SOCS family members examined, only SOCS-3 mRNA was strongly and rapidly induced by OSM. SOCS-3 protein was present within 1h and rapidly declined thereafter. Constitutive expression of SOCS-3 protein completely abolished the activation of the Jak-STAT signaling pathway as well as the Ras-MAP kinase pathway. As a result, A375 cells acquired an OSM-resistant phenotype. Our findings demonstrate that SOCS-3 is a potent regulator of OSM response and suggest that dysregulation of SOCS-3 expression could provide a mechanism for OSM resistance acquisition during tumour progression.
Magrangeas
F
F
INSERM U. 463, Institut de Biologie, 9, quai Moncousu, 44093 Nantes Cedex 01, France.
Boisteau
O
O
Denis
S
S
Jacques
Y
Y
Minvielle
S
S
D001483:Base Sequence; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053683:Oncostatin M; D010455:Peptides / Q000378:metabolism*; D011506:Proteins / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
D017931:DNA Primers; C508351:OSM protein, human; D010455:Peptides; D011506:Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D053683:Oncostatin M; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases