Biomedical subjects

F Uberall

Publications and source records attributed to F Uberall.

40 records · Page 3Linked to original sources

PubMed1990

Mechanism and biological significance of the Ha-ras-induced activation of the Na+/H(+)-antiporter.

Expression of the transforming Ha-ras oncogene in MMTV-LTR transfected NIH 3T3 cells leads to a growth factor independent activation of the Na+/H(+)-antiporter. The activation of the antiporter is insensitive to the protein kinase inhibitor staurosporine and equally expressed in protein kinase C-depleted cells. It is concluded that the Ha-ras induced activation of the antiporter occurs by a protein kinase C-independent mechanism. An inhibition of the Na+/H(+)-antiporter by dimethylamiloride or a reduction of the extracellular [Na+] concentration results in a depression of the bombesin induced release of Ca2+ from intracellular stores. These results are explained by a steep pH-dependence of the Ca2(+)-mobilizing system which exhibits a maximum at pH 7.1 in the system studied here. Stimulation by growth factors of quiescent cells with a resting pH below 7 results in a shift of the cytosolic pH towards the optimum for the Ca2+ release. In agreement with the proposed interrelationship, pHi and [Ca2+]i rise and peak simultaneously after addition of bombesin to G0 arrested cells.

Alkaloids↗

PubMed1989

Ha-ras activates the Na+/H+ antiporter by a protein kinase C-independent mechanism.

In quiescent Ha-ras-transfected NIH 3T3 cells, addition of serum growth factors, bombesin or 12-O-tetradecanoylphorbol-13-acetate (TPA) leads to a dimethylamiloride-sensitive intracellular alkalinization which can be inhibited by staurosporine, a potent inhibitor of protein kinase C. Expression of the transforming Ha-ras gene causes a growth factor-independent increase in cytoplasmic pH. This Ha-ras-induced alkalinization is sensitive to dimethylamiloride but is not affected by staurosporine concentrations which prevent the pH response after addition of growth factors or TPA. Protein kinase C depletion by long term exposure to TPA eliminates the pH response to bombesin and phorbol ester but does not effect the Ha-ras-induced intracellular alkalinization. It is concluded that expression of Ha-ras causes an activation of the Na+/H+ antiporter by an as yet unknown protein kinase C-independent mechanism.

Alkaloids↗

PubMed1989

The phospholipid- and calcium-dependent protein kinase as a target in tumor chemotherapy.

Evidence for a constitutive activation of protein kinase C (EC 2.7.1.37) in Ha-ras transformed 3T3 cells is presented. Several compounds which inhibit protein kinase C in vitro have been studied with regard to their antiproliferative activity in cultured tumor cells. The following agents were investigated: 3-hexadecyl-mercapto-2-methoxy-methyl-propyl-1- phosphocholine (BM 41440); 1-octadecyl-2-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3); quercetin, tamoxifen and staurosporine. All compounds decrease protein kinase C activity in vitro as well as in intact cells and inhibit cell multiplication within the same dose range. The results suggest a causal relation between the antiproliferative effects and the inhibition of protein kinase C. All inhibitors of protein kinase C synergistically enhance the antiproliferative activity of cis-diamminedichloroplatinum(II). Available data suggest that the effects of protein kinase C inhibitors should be exploitable for tumor chemotherapy.

Animals↗

PubMed1988

Enhancement of the antiproliferative effect of cis-diamminedichloroplatinum(II) and nitrogen mustard by inhibitors of protein kinase C.

Quercetin (3,3',4',5,7-pentahydroxyflavone) has been shown to inhibit a variety of enzymes including the calcium- and phospholipid-dependent protein kinase (protein kinase C) in vivo and in vitro. We show that this compound synergistically enhances the antiproliferative activity of cis-diamminedichloroplatinum(II) (cis-DDP) and nitrogen mustard. Quercetin does not affect the repair of DNA interstrand cross-links introduced by cis-DDP. Long-term exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA), which reduces total protein kinase C activity, also amplifies the growth-inhibitory effect of cis-DDP and acts synergistically with quercetin. A synergism is also observed if tamoxifen or staurosporine are combined with cis-DDP. For both drugs the dose-effect curves for the inhibition of protein kinase C closely resemble the dose-effect curves for the antiproliferative activities. Although alternative mechanisms cannot be definitively excluded, the effects of quercetin, TPA, tamoxifen and staurosporine may result from the inhibition of protein kinase C.

Alkaloids↗