Inhibition of p38-MAPK potentiates cisplatin-induced apoptosis via GSH depletion and increases intracellular drug accumulation in growth-arrested kidney tubular epithelial cells.

We were interested in analyzing the regulation by mitogen-activated protein kinases (MAPKs) of cisplatin-provoked toxicity in epithelial renal tubule cell lines, when assayed under culture conditions (cell confluence plus serum deprivation), which mimic the characteristics of a nonproliferating epithelium. Under these restrictive growth conditions, cisplatin induced apoptosis with lower efficacy than in exponentially growing cells, and decreased p38-MAPK phosphorylation in NRK-52E and other (LLC-PK1, MDCK, HK2) cell lines. Moreover, cisplatin-provoked apoptosis was potentiated by cotreatment with p38-MAPK-specific inhibitors (SB203580, SB220025) or transfection with a kinase-negative mutant of MKK6, whereas c-Jun NH2-terminal kinase or extracellular signal-regulated kinase/MAPK and ERK Kinase inhibitors were ineffective.

Regulation of cadmium-induced apoptosis by PKCdelta in U937 human promonocytic cells.

Pulse treatment with cadmium chloride followed by recovery caused apoptosis in U937 human promonocytic cells. In addition, the treatment-induced PKCdelta translocation from cytosol to membrane fraction, which was already detected at 30 min of treatment; and also caused PKCdelta cleavage to give a 41-kDa fragment, which was detected at 3-6 h of recovery, concomitantly with the execution of apoptosis. All these effects were reduced by the PKCdelta-specific inhibitor rottlerin.

Effect of chronic alcohol consumption on Go protein in rat brain.

Almost all of the important pathophysiological targets for ethanol in the nervous system appear to be specific membrane proteins involved in signal transduction. In this paper we have examined levels and functionality of the alpha subunit of the Go protein (Goalpha) in cerebral cortex and cerebellum from rats that have chronically ingested ethanol, by using immunoblotting and pertussis toxin-catalyzed ADP-ribosylation experiments. Goalpha protein levels were increased in plasma membranes from the two brain areas, and this increase was shown to specifically affect Go1alpha, one of the two isoforms of the Goalpha subunit.