Possible role of protein kinase C zeta in muscarinic receptor-induced proliferation of astrocytoma cells.
Recent studies have shown that protein kinase C zeta (PKC zeta) is part of a pathway that plays a key role in a wide range of physiological processes including mitogenesis, cell survival, and transcriptional regulation. Most studies on PKC zeta have been done by stimulating cells with tyrosine kinase receptor agonists, or by transfecting the cells with either constitutively active PKC zeta or negative mutants of PKC zeta. Less is known about the ability of endogenous G-protein-coupled receptors to generate a mitogenic signal through activation of endogenous PKC zeta. In the present paper, we showed that in 123-1N1 human astrocytoma cells, which express the G-protein-coupled M2, M3, and M5 muscarinic receptors, PKC zeta is activated by carbachol in a concentration-dependent manner, resulting in the translocation of PKC zeta from the cytoplasm to granules in the perinuclear region. The effect of carbachol was long-lasting (up to 24 hr) and appeared to be mediated by activation of M3 muscarinic receptors. A selective PKC zeta inhibitor peptide (peptide Z) inhibited PKC zeta translocation as well as carbachol-induced DNA synthesis. Inhibition of both phosphatidylinositol 3-kinase and phospholipase D decreased carbachol-induced [(3)H]thymidine incorporation and blocked carbachol-induced PKC zeta translocation, suggesting an involvement of both pathways in these effects.
Guizzetti
M
M
Department of Environmental Health, University of Washington, Seattle, WA 98105, USA. marina@u.washington.edu
Costa
L G
LG
D001254:Astrocytoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018721:Muscarinic Agonists / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000099221:Protein Kinase C zeta
D018721:Muscarinic Agonists; D010712:Phosphatidic Acids; D019869:Phosphatidylinositol 3-Kinases; D010739:Phospholipase D; D011493:Protein Kinase C; D011976:Receptors, Muscarinic; D000099221:Protein Kinase C zeta