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E A Gordon

Publications and source records attributed to E A Gordon.

25 records · Page 2Linked to original sources
PubMed1986

Thrombin-receptor occupancy initiates a transient increase in cAMP levels in mitogenically responsive hamster (NIL) fibroblasts.

Previous studies from our laboratory have shown that thrombin mitogenesis requires both high-affinity receptor occupancy and enzymic activity. Combined addition of DIP-inactivated-thrombin, which retains the ability to bind to thrombin receptors, and enzymically active gamma-thrombin generates a complete set of signals sufficient to initiate cell proliferation. Several possible signals, including stimulation of ion fluxes and phosphoinositide turnover, appear to be stimulated by thrombin's enzymic activity, but not by receptor occupancy. We now report that alpha-thrombin and DIP-thrombin stimulate an early, transient increase of 60 to 200% in intracellular levels of cAMP. This stimulation occurs at low mitogenic concentrations of alpha-thrombin where less than half the receptors are occupied. Enzymically active gamma-thrombin, which stimulates other types of signals, has no stimulatory effects on cAMP. Thus, this effect appears to be generated by high-affinity interaction of thrombin with its cell-surface receptors. Artificially increasing cAMP levels within these cells, however, cannot replace the requirement for thrombin-receptor occupancy in completing the mitogenic stimulation. Therefore, thrombin-receptor occupancy may generate additional, as yet unidentified, required signals.

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PubMed1985

Phosphoinositides in mitogenesis: neomycin inhibits thrombin-stimulated phosphoinositide turnover and initiation of cell proliferation.

Thrombin stimulates 32Pi incorporation into phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4,5-bis-phosphate (PIP2), and phosphatidylinositol (PI), and initiates DNA synthesis in hamster (NIL) fibroblasts at a half-maximal concentration of 125 ng/ml. Neomycin, which binds PIP2 and PIP, inhibits both thrombin-stimulated initiation of cell proliferation and 32P pI incorporation into at concentrations above 2 mM without affecting thrombin binding, thymidine uptake, or cellular protein synthesis. At lower concentrations, neomycin inhibits thrombin-stimulated release of inositol 1,4,5-trisphosphate (IP3), by selectively binding PIP2, but does not inhibit 32P incorporation into PI or initiation of DNA synthesis. Phosphoinositide recycling and diacylglycerol release therefore appear necessary for initiation of cell proliferation by thrombin. IP3-stimulated Ca++ mobilization may not be required for thrombin mitogenesis, however, since neomycin can block IP3 release without inhibiting initiation.

Animals↗