Effects of adenylyl cyclase and protein kinase A inhibition on signaling enzymes in natural killer cells: comparison to tributyltin
| Autor: | Margaret M. Whalen, Sabah O. Odman-Ghazi |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty Cell Survival Health Toxicology and Mutagenesis Biology Toxicology Antiviral Agents 01 natural sciences Natural killer cell Adenylyl cyclase chemistry.chemical_compound Cell Line Tumor Internal medicine medicine Humans Cytotoxic T cell Phosphorylation Protein kinase A Phospholipase C 010405 organic chemistry 010401 analytical chemistry General Medicine Cyclic AMP-Dependent Protein Kinases Molecular biology 0104 chemical sciences Killer Cells Natural medicine.anatomical_structure Endocrinology chemistry Adenylyl Cyclase Inhibitors Dideoxyadenosine Trialkyltin Compounds Tyrosine kinase |
| Zdroj: | Human & Experimental Toxicology. 25:333-340 |
| ISSN: | 1477-0903 0960-3271 |
| DOI: | 10.1191/0960327106ht630oa |
| Popis: | Natural killer (NK) cells are lymphocytes capable of destroying tumor cells and virally-infected cells without prior sensitization. In a previous study, we found that inhibition of adenylyl cyclase (AC) or cAMP-dependent protein kinase (PKA) decreased the ability of NK cells to destroy tumor cells. We also found that the environmental contaminant tributyltin (TBT), at concentrations of 300 500 nM, decreased tumor-cell lysis by NK cells, as well as their intracellular levels of cAMP. This suggested that the decreases in cAMP associated with TBT (300 500 nM) may, in part, be responsible for loss of cytotoxic function. Here, we investigated the effects of inhibition of AC or PKA on enzymes that are required in the NK tumorolytic process and compared them to those of TBT exposure. The enzymes studied were: the protein tyrosine kinase (PTK), syk; phospholipase C gamma1(PLCg1); and the mitogen activated protein kinase (MAPK), p44/42. Exposure of NK cells to the AC inhibitor 2?,5?-dideoxyadenosine (DDA) significantly increased the total level of PLCg1by 67% after 60 min and the level of p44/42 by about 30%. Exposure to the PKA inhibitor H-89 significantly increased the levels of the phosphorylated (activated) p44/42 (90%) after 60 min. Exposure to TBT increased the levels of PLCg1by about 50%. Previously, we found that exposure to TBT increased the phosphorylation of p44/42 within 5 min. These results indicate that AC inhibition caused alterations of the levels of key enzymes, while decreased PKA activity caused an increase in p44/42 activation. They also suggest that the effects of decreased levels of cAMP on these key cytotoxic signaling proteins may overlap, to a very limited extent, with those of TBT. |
| Databáze: | OpenAIRE |
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