Expression and localization of Ski determine cell type-specific TGFbeta signaling effects on the cell cycle.
Transforming growth factor beta (TGFbeta) promotes epithelial cell differentiation but induces Schwann cell proliferation. We show that the protooncogene Ski (Sloan-Kettering viral oncogene homologue) is an important regulator of these effects. TGFbeta down-regulates Ski in epithelial cells but not in Schwann cells. In Schwann cells but not in epithelial cells, retinoblastoma protein (Rb) is up-regulated by TGFbeta. Additionally, both Ski and Rb move to the cytoplasm, where they partially colocalize. In vivo, Ski and phospho-Rb (pRb) appear to interact in the Schwann cell cytoplasm of developing sciatic nerves. Ski overexpression induces Rb hyperphosphorylation, proliferation, and colocalization of both proteins in Schwann cell and epithelial cell cytoplasms independently of TGFbeta treatment. Conversely, Ski knockdown in Schwann cells blocks TGFbeta-induced proliferation and pRb cytoplasmic relocalization. Our findings reveal a critical function of fine-tuned Ski levels in the control of TGFbeta effects on the cell cycle and suggest that at least a part of Ski regulatory effects on TGFbeta-induced proliferation of Schwann cells is caused by its concerted action with Rb.
Jacob
Claire
C
Department of Biology, Institute of Cell Biology, ETH Zurich, CH-8093 Zurich, Switzerland. claire.jacob@cell.biol.ethz.ch
Grabner
Henrik
H
Atanasoski
Suzana
S
Suter
Ueli
U
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D009186:Myelin Sheath / Q000378:metabolism; D009928:Organ Specificity; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology* / Q000378:metabolism; D012584:Sciatic Nerve / Q000196:embryology / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; C525545:Ski protein, rat; D016212:Transforming Growth Factor beta; D012694:Serine