Abstract
Upon entering a cell the natural product rapamycin, like the structurally related immunosuppressant FK506, associates with members of the FKBP family of proteins. One or more of the resulting FKBP-rapamycin complexes blocks signaling pathways emanating from some growth factor receptors. Recently, the addition of rapamycin was shown to inhibit the phosphorylation and activation of a 70-kDa ribosomal S6 protein kinase, which normally occurs minutes after the activation of certain cytokine and growth factor receptors. We now report that rapamycin can be added 4 to 6 h after the addition of serum growth factors to quiescent human osteosarcoma cells and still arrest these cells in G1. This window of action correlates with the inducible appearance of a cyclin-dependent kinase (cdk) activity, and the induction of this activity is inhibited by the addition of rapamycin. Furthermore, p36cyclin D1 associates with this cdk protein complex in lysates of untreated cells, but does not associate with this cdk protein complex in lysates of rapamycin-treated cells. Together, these studies demonstrate that FKBP-rapamycin can modulate a cyclin-dependent kinase activity and a cyclin D1-cdk association during early G1 in MG-63 human osteosarcoma cells.
Highlights
Oneormoreof the resulting FKBP-rapamycincom- insulinstimulation of quiescenthepatocytes
Rapamycin (5 nM) treatment of MG-63 cells synchronized by serum starvation prevented entry into S phase as determined by flowcytometry (Fig.1C).A 1000-foldexcess of FK506, which alone does not cause G1 arrest in these cells, reversed the rapamycin-induced G1 blockade (Fig. lD),suggestingthat rapamycin is notcytotoxic and that one or more FKJ3Ps mediates rapamycin's actions [12]
Rapamycin blocked S phase entry whenadded as late as 4 h following serum stimulation of quiescent MG-63 cells (Table I), indicating that the first rapamycin-sensitive signalingeventsnecessary for G1 progression occur after 4 h following serum stimulationof quiescent MG-63 cells
Summary
Oneormoreof the resulting FKBP-rapamycincom- insulinstimulation of quiescenthepatocytes
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