Mitotic aberrations induced by carbaryl reflect tyrosine kinase inhibitionwith coincident up-regulation of serine threonine protein phosphatase activity: implications for coordination of karyokinesis and cytokinesis
A. Renglin et al., Mitotic aberrations induced by carbaryl reflect tyrosine kinase inhibitionwith coincident up-regulation of serine threonine protein phosphatase activity: implications for coordination of karyokinesis and cytokinesis, MUTAGENESIS, 14(3), 1999, pp. 327-333
The insecticide carbaryl and its metabolite 1-naphthol cause partial uncoup
ling of karyokinesis and cytokinesis in V79 Chinese hamster fibroblasts; ka
ryokinesis is blocked in metaphase, the microtubules of the spindle depolym
erize and the chromosomes and spindle remnants become displaced to the peri
phery of the cell. A high frequency of these disturbed cells elongate and a
smaller fraction initiate a cleavage furrow. Here, we attempt to determine
the potential targets for carbaryl and 1-naphthol in cytokinesis-specific
signalling, led by the fact that the potential protein phosphatase inhibito
r 1-naphthyl phosphate was previously identified in treated cells. We found
that the typical cytological pattern induced by carbaryl and 1-naphthol co
uld be obtained with tyrphostins, specific tyrosine kinase inhibitors, indi
cating that the carbaryl-induced effects could be due to tyrosine kinase in
hibition. This was confirmed by tyrosine kinase assays showing that carbary
l, 1-naphthol and 2-naphthol were equally efficient at inhibiting tyrosine
kinase activity as tyrphostin B44(-). As tyrosine kinases can act as regula
tory factors in determining dephosphorylation rates, the activities of type
-1 (PP1) and type-2A (PP2A) serine/threonine protein phosphatases were also
determined. There was a clear up-regulation of the overall PP1/PP2A activi
ties in cells treated with carbaryl, 1-naphthol or tyrphostin B44(-), This
stimulation was shown to be indirect because these compounds had no effect
on the activity of purified human PP1 in the test tube. 2-Naphthol, which h
as been found to be less efficient with regard to displacement of chromatin
, did not cause up-regulation, but a significant decrease in PP1/PP2A activ
ity. We suggest that a net decrease in tyrosine kinase activity in combinat
ion with a net increase in PP1/PP2A activity is a precondition for cell elo
ngation and cytokinesis in mammalian cells and that the corresponding enzym
es are targets in the network of activities serving to coordinate karyokine
sis and cytokinesis.