Oncostatin M regulates membrane traffic and stimulates apicalization of the cell surface in hepatoma cells in a protein kinase A-dependent manner. Here, we show that oncostatin M enhances the expression of the cyclin-dependent kinase (cdk)2 inhibitor p27 Kip1 , which inhibits G 1 -S phase progression. Forced G 1 -S-phase transition effectively renders presynchronized cells insensitive to the apicalization-stimulating effect of oncostatin M. G 1 -S-phase transition prevents oncostatin M-mediated recruitment of protein kinase A to the centrosomal region and precludes the oncostatin M-mediated activation of a protein kinase A-dependent transport route to the apical surface, which exits the subapical compartment (SAC). This transport route has previously been shown to be crucial for apical plasma membrane biogenesis. Together, our data indicate that oncostatin M-stimulated apicalization of the cell surface is critically dependent on the ability of oncostatin M to control p27 Kip1 /cdk2-mediated G 1 -S-phase progression and suggest that the regulation of apical plasma membrane-directed traffic from SAC is coupled to centrosome-associated signaling pathways.
INTRODUCTIONThe establishment and maintenance of apical and basolateral plasma membrane (PM) domains in epithelia require a careful orchestration of extra-and intracellular signals, triggering crucial cytoskeleton-, organelle-, and membrane traffic-linked machineries, as partly elucidated in systems as diverse as yeast, Drosophila, and mammalian cells (Lecuit and Pilot, 2003;Mostov et al., 2003;Baas et al., 2004). Impairment of these events may cause a loss of apical-basolateral asymmetry and may lead to deranged cell growth (Bilder et al., 2000;Vermeer et al., 2003;Baas et al., 2004) or spindle misorientation . Recent studies have reported an evolutionary conserved genetic program that may link the process of polarity development and proliferation (Bilder et al., 2000;Humbert et al., 2003;Rolls et al., 2003;Klezovitch et al., 2004). However, many aspects of such a link remain unclear, e.g., the extent to which cell proliferation can directly affect epithelial cell organization or vice versa. Indeed, epithelial cell proliferation and apical-basolateral polarity may be controlled by different signaling pathways (Liu et al., 2004).Signaling cascades stimulated by interleukin-6 family cytokines, including oncostatin M (OSM), elicit multiple responses in the cell. Originally, as its name indicates, oncostatin M was primarily recognized to inhibit the proliferation of tumor cells (Tanaka and Miyajima, 2003), presumably by modulating cell cycle regulatory proteins, including the cyclin-dependent kinase (cdk)2-inhibitor p27 Kip1 (Kortylewski et al., 1999;Klausen et al., 2000;Li et al., 2001). Disruption of the regulatory system that controls G 1 -phase progression is a common event in human hepatocarcinogenesis (Hui et al., 1998), and p27 Kip1 has been associated with differentiation, invasiveness, and metastasis of hepatocellular carcinoma tumors (Zhou et al., 2003). ...