Abstract
Oncostatin M has been characterized as a potent growth inhibitor for various tumor cells. Oncostatin M-treated glioblastoma cells cease proliferation and instigate astrocytal differentiation. The oncostatin M-induced cell cycle arrest in G(1) phase is characterized by increased level of the cyclin-dependent kinase (CDK) inhibitory proteins p21(Cip1/Waf1/Sdi1) and p27(Kip1). Induction of p21 protein corresponds to increased mRNA level, whereas p27 accumulates due to increased stability of the protein. Interestingly, stabilization of p27(Kip1) occurs even in S phase, showing that p27 stabilization is a direct consequence of oncostatin M signaling and not a result of the cell cycle arrest. Degradation of p27 in late G(1) and S phase is initiated by the ubiquitin ligase complex SCF-Skp2/Cks1. Oncostatin M inhibits expression of two components of this E3 ligase complex (Skp2 and Cks1). Although combined overexpression of Skp2 and Cks1 rescues p27 degradation in S phase, it can not override p27 accumulation in G(1) phase and cell cycle arrest by oncostatin M. In addition to increasing Cdk inhibitor level, oncostatin M also impairs cyclin A expression. Cyclin A mRNA and protein level decline shortly after oncostatin M addition. The accumulation of two CDK inhibitor proteins and the repression of cyclin A expression may explain the broad and potent antiproliferative effect of the cytokine.
MeSH terms
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Antineoplastic Agents / pharmacology*
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CDC2-CDC28 Kinases
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Carrier Proteins / antagonists & inhibitors*
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Carrier Proteins / biosynthesis
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Cell Cycle / drug effects
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Cell Growth Processes / drug effects
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Cell Line, Tumor
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Cyclin A / antagonists & inhibitors*
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Cyclin A / biosynthesis
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Cyclin A / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis*
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / antagonists & inhibitors
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / biosynthesis
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Cytokines / pharmacology*
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Down-Regulation / drug effects
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Glioblastoma / drug therapy*
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Glioblastoma / genetics
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Humans
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Oncostatin M
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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S-Phase Kinase-Associated Proteins / antagonists & inhibitors*
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S-Phase Kinase-Associated Proteins / biosynthesis
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S-Phase Kinase-Associated Proteins / genetics
Substances
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Antineoplastic Agents
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CDKN1A protein, human
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CKS1B protein, human
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Carrier Proteins
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Cyclin A
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Cyclin-Dependent Kinase Inhibitor p21
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Cytokines
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OSM protein, human
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RNA, Messenger
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RNA, Small Interfering
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S-Phase Kinase-Associated Proteins
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Oncostatin M
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Cyclin-Dependent Kinase Inhibitor p27
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CDC2-CDC28 Kinases
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Cyclin-Dependent Kinases