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Oncostatin M Induces Growth Arrest by Inhibition of Skp2, Cks1, and Cyclin A Expression and Induced p21 Expression

¹ Department of Neurology, Westfälische Wilhelms-Universität Münster, Münster, Germany; ² Max Planck Institute for Biochemistry, Martinsried, Germany; and ³ Division of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria

Requests for reprints: Ludger Hengst, Division of Medical Biochemistry, Innsbruck Medical University, Fritz Pregl Str. 3, Innsbruck, Austria 6020. Phone: 43-512-507-3270; Fax: 43-512-507-2872; E-mail: ludger.hengst{at}i-med.ac.

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 G₁ 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 G₁ 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 G₁ 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. (Cancer Res 2006; 66(13): 6530-9)