An extensive investigation of the cardiac actions of phorbol esters and the potential role of the Na+-H+ exchanger in those actions was carried out using isolated rat hearts. Sixty minutes of perfusion with 10-` M phorbol 12-myristate 13-acetate (PMA) or 10-8 M phorbol 12,13-dibutyrate (PDBu) produced marked cardiac dysfunction associated with depressed contrac-tility, coronary constriction, an...

In vitro megakaryocyte differentiation is regulated by two activities: a megakaryocyte colony-stimulating activity (Mk-CSA), which is required for proliferation, and an auxiliary factor, megakaryocyte potentiating activity, which plays a role in later differentiation events. Tumor-promoting phorbol esters alter many cellular differentiation-related events. Thus, it was hypothesized that phorbol...

In vascular smooth muscle, phorbol esters cause a slowly developing contraction and an associated transmembrane calcium flux, both of which are inhibited by dihydropyridine calcium channel antagonists. In the A7r5 cultured vascular cell line, we used the whole-cell voltage-clamp technique to identify voltage-dependent calcium conductances and investigate the effect of phorbol esters on that con...

Phospholipase D (PLD) activity, as measured by the transphosphatidylation of cellular phospholipids, is elevated in BALB/c 3T3 cells transformed by v-Src. Phorbol esters that activate protein kinase C (PKC) also increase PLC activity in BALB/c 3T3 cells. v-Src-induced PLD activity could be distinguished from phorbol ester-induced PLD activity by differential radiolabelling of phospholipids, whi...

In exploring the biological basis of androgen-independent prostate cancer, we observed serum-independent growth of androgen-independent cells. We then discovered that in androgen-independent but not androgen-dependent cells, the serum-responsive gene c-fos is insensitive to phorbol esters, which regulate c-fos through the same mechanisms as serum. Transient expression of protein kinase C, throu...

The rate of metabolic acid generation by neutrophils increases greatly when they are activated. Intracellular acidification is prevented in part by Na+/H+ exchange, but a sizable component of H+ extrusion persists in the nominal absence of Na+ and HCO3-. In this report we determined the contribution to H+ extrusion of a putative H+ conductive pathway and its mode of activation. In unstimulated ...

The phorbol esters 12-O-tetradecanoylphorbol-13-acetate, phorbol 12,13-didecanoate, phorbol 12,13-dibutyrate (PDB), and phorbol 12,13-dibenzoate were found to compete with [20-3H]-PDB binding to human myeloblastic leukemia ML-1 cells in approximate proportion to their differentiation-inducing capacity. Fetal bovine serum decreased the down modulation of phorbol ester receptor sites on these cel...

Despite the relevant therapeutic progresses made in these last 2 decades, the prognosis of acute myeloid leukemia (AML) remains poor. Phorbol esters are used at very low concentrations as differentiating agents in the therapy of myeloid leukemias. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), in turn, is a death ligand that spares normal cells and is therefore currently under...

The protein kinase C (PKC) family of serine/threonine kinases is an attractive drug target for the treatment of cancer and other diseases. Diacylglycerol (DAG), phorbol esters and others act as ligands for the C1 domain of PKC isoforms. Inspection of the crystal structure of the PKCδ C1b subdomain in complex with phorbol-13-O-acetate shows that one carbonyl group and two hydroxyl groups play pi...

We have used primary cultures of swine granulosa cells to investigate the regulatory role of the protein kinase C pathway in the ovary. In this system, we observed the following. Swine granulosa cells bound [3H]phorbol 12,13-dibutyrate [( 3H]PDB) specifically with high affinity [apparent Ki for 12-O-tetradecanoylphorbol 13-acetate (TPA) = 3.1 (2.1-4.7) nM] and low capacity [0.68 (0.34-0.99) pmo...