European Journal of Immunology · 2006 · 21 citations · 53 references
Life SciencesCell BiologyImmunologyCell SignalingImmunoregulationSignal TransductionCell Signaling NetworksCyclin-dependent KinasesCytokine BiologyCytokine SignalingGrowth Factor SignalingMacrophage BiologyCdk ActivationCdk InactivationCell Cycle DynamicsCell Cycle InhibitionCyclin-dependent Kinase ActivationMacrophage ProliferationMap KinasesRaf-mek-erk Signaling
The immunosuppressor sanglifehrin A (SfA) is a member of a family of immunophilin cyclophilin A-binding molecules and does not inhibit calcineurin activity. Sanglifehrin A inhibits M-CSF-dependent macrophage proliferation by arresting the G1 phase of the cell cycle but does not affect cell viability. This immunosuppressor exerts its action on proliferation by inactivating cyclin-dependent kinase 2 (Cdk2) activity. Moreover, c-myc expression is also repressed. In the early steps of M-CSF signaling, SfA inhibits the phosphorylation of Raf-1 and the external regulated kinases (ERK)1/2 and mitogen-activated protein kinase phosphatase-1, which are required for proliferation. The effects of SfA are not related to a block of the proteosome activity. These data show that immunophilin contributes to M-CSF-dependent proliferation through activation of the Raf-1/MEK/ERK pathway and the regulation of Cdk activities, which is required for cell cycle progression.
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SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27
Andrea C. Carrano, Esther Eytan, Avram Hershko et al. · Nature Cell Biology · 1999 · 1.5K citations