PDGF initiates two distinct phases of protein kinase C activity that make unequal contributions to the G0 to S transition
| Autor: | Steven Jones, Egle Balciunaite, Andrius Kazlauskas, Alex Toker |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Time Factors
Blotting Western Protein Kinase C-epsilon Biology Resting Phase Cell Cycle General Biochemistry Genetics and Molecular Biology S Phase Diglycerides Phosphatidylinositol 3-Kinases Enzyme activator Tumor Cells Cultured Humans Receptors Platelet-Derived Growth Factor Protein Kinase C Protein kinase C Nucleic Acid Synthesis Inhibitors Diacylglycerol kinase Platelet-Derived Growth Factor Agricultural and Biological Sciences(all) DNA synthesis Biochemistry Genetics and Molecular Biology(all) PKCS Lipid Metabolism Precipitin Tests Molecular biology Cell biology Enzyme Activation Isoenzymes biology.protein Signal transduction General Agricultural and Biological Sciences Platelet-derived growth factor receptor Signal Transduction |
| Zdroj: | Current Biology. (5):261-267 |
| ISSN: | 0960-9822 |
| DOI: | 10.1016/S0960-9822(00)00358-4 |
| Popis: | Background: Platelet-derived growth factor (PDGF) promotes cell-cycle progression by engaging signaling enzymes such as phospholipase Cγ (PLCγ). When activated, PLCγ cleaves phosphatidylinositol-4,5-bisphosphate to produce inositol-1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 stimulates the release of calcium from intracellular stores, which together with DAG activate some protein kinase C (PKC) family members. In this study we focused on putative downstream effectors of PLCγ PKC family members. We investigated whether, and when, DAG-responsive PKCs contribute to PDGF-dependent DNA synthesis. Results: In HepG2 cells expressing wild-type PDGF β receptors (βPDGFRs), PDGF activated at least one PKC family member (PKCϵ) at two distinct times — within 10 minutes after PDGF stimulation, and then for a longer duration between 5 and 9 hours. Blocking the early burst of PKC activity had no effect on PDGF-dependent DNA synthesis. In contrast, the DNA-synthesis response was reduced by 60–80% when the second phase of PKC activity was blocked. Similarly, DAG rescued PDGF-dependent DNA synthesis in the cells expressing a mitogenically incompetent mutant βPDGFR, but only when DAG was added at times corresponding to the late phase of PKC activity. Our studies also indicate that the late phase of PKCϵ activity can be induced by either phosphoinositide 3-kinase-dependent or DAG-dependent pathways in PDGF-stimulated HepG2 cells. Conclusions: We conclude that PDGF activates PKCs at two distinct times and that these two intervals of PKC activity make unequal contributions to the mitogenic response. The late phase of PKC activity is required for PDGF-dependent DNA synthesis, whereas the early phase of activity is dispensable. |
| Databáze: | OpenAIRE |
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