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Inhibitors of ser/thr phosphatases 1 and 2A induce apoptosis in pituitary GH3 cells.
- Source :
-
Naunyn-Schmiedeberg's archives of pharmacology [Naunyn Schmiedebergs Arch Pharmacol] 1997 Jul; Vol. 356 (1), pp. 8-16. - Publication Year :
- 1997
-
Abstract
- Two structurally different inhibitors of ser/thr phosphatases 1 and 2A, okadaic acid and calyculin A, time- and concentration-dependently stimulated and inhibited cell-specific function (hormone gene expression) in pituitary GH3 cells. The negative effect was associated with the appearance of apoptotic cell death. Nanomolar concentrations of both agents produced the characteristic morphological alterations and a DNA fragmentation ladder. Calyculin A treatment resulted in comparable changes with 10fold lower concentrations than okadaic acid. Observations with derivatives of okadaic acid with no or lower phosphatase inhibitory potency supported the conclusion that apoptosis induction is related to inhibition of ser/thr phosphatases, presumably types 1 and 2A. Membrane damage as measured by lactate dehydrogenase liberation into medium was significantly lower in apoptotic vs. necrotic cells. DNA fragmentation could be reduced by the addition of zinc but not by removal of extracellular calcium with EGTA. Apoptotic changes were reduced by the concomitant activation of protein kinase A by a membrane permeable cAMP analogue. Incubation of cells for 4 months in successively increased concentrations of okadaic acid resulted in a population that proliferated at the initially lethal concentration of 30 nM.
- Subjects :
- Animals
Cell Survival drug effects
Cells, Cultured
DNA Fragmentation drug effects
Enzyme Inhibitors pharmacology
In Vitro Techniques
L-Lactate Dehydrogenase metabolism
Marine Toxins
Okadaic Acid pharmacology
Oxazoles pharmacology
Pituitary Gland drug effects
Pituitary Gland enzymology
Plasmids
Rats
Transfection
Apoptosis drug effects
Phosphoprotein Phosphatases antagonists & inhibitors
Pituitary Gland cytology
Subjects
Details
- Language :
- English
- ISSN :
- 0028-1298
- Volume :
- 356
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Naunyn-Schmiedeberg's archives of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 9228184
- Full Text :
- https://doi.org/10.1007/pl00005032