Oncostatin M (OSM) cytostasis of breast tumor cells: characterization of an OSM receptor beta-specific kernel.
The interleukin-6 cytokine oncostatin M (OSM) induces potent growth-inhibitory and morphogenic responses in several different tumor cell types, highlighting the importance of OSM signaling mechanisms as targets for therapeutic intervention. The specific molecular pathways involved are not well understood, as OSM can signal through two separate heterodimeric receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) alpha and gp130/OSM receptor beta (OSMRbeta). In this investigation, we used a LIFR antagonist to help resolve signaling responses and identify patterns of gene expression elicited by the different receptor complexes. OSM-induced biological effects on breast tumor-derived cell lines were specifically mediated through the gp130/OSMRbeta complex. Each cytokine tested exhibited differential signaling capability and manifested both shared and unique patterns of gene activation, emphasizing compositional differences in activator protein-1 transcription factor activity and expression. In particular, OSM strongly activated the c-Jun NH(2)-terminal kinase (JNK) serine/threonine kinase and downstream components, including activating transcription factor (ATF)/cyclic AMP-responsive element binding protein family member, ATF3. JNK/stress-activated protein kinase kinase inhibition abrogated cell morphogenesis induced by OSM, indicating an important role for this pathway in OSM specificity. These findings identify a core signaling/transcriptional mechanism specific to the OSMRbeta in breast tumor cells.
Underhill-Day
Nicholas
N
Cancer Research UK Growth Factor Group, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom. N.UnderhillDay@bham.ac.uk
Heath
John K
JK
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053683:Oncostatin M / Q000494:pharmacology*; D053681:Oncostatin M Receptor beta Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053606:Receptors, OSM-LIF / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D015850:Interleukin-6; C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C508348:OSMR protein, human; D053681:Oncostatin M Receptor beta Subunit; D053606:Receptors, OSM-LIF; D050791:STAT Transcription Factors; D053683:Oncostatin M; D020928:Mitogen-Activated Protein Kinases