RasGRP represents the prototype of a new class of guanine nucleotide exchange factors that activate small GTPases. The guanyl nucleotide-releasing protein (GRP) family members contain catalytic domains related to CDC25, the Ras exchange factor of Saccharomyces cerevisiae. They also contain a motif resembling a pair of calcium-binding EF-hands and a C1 domain similar to the diacylglycerol intera...

The human, leukemic cell line, HL-60, undergoes differentiation in response to tumor-promoting phorbol esters. Recent studies have implicated stimulation of a Na+/H+ antiporter as an initial event in cellular differentiation and/or proliferation. The effects of phorbol esters on Na+-dependent H+ efflux from HL-60 cells were studied by pH-stat titration. Tumor-promoting phorbol diesters, but not...

Phorbol esters inhibit chemically induced differentiation in Friend erythroleukemia cells. This study examines the effect of the macrocyclic lactone bryostatin 1 on phorbol ester responses in a Friend erythroleukemia cell clone, PS 7. In several biological systems, bryostatin 1 was reported to mimic phorbol ester action, including activation of protein kinase C, but in HL-60 cells it blocked ph...

Phorbol esters inhibit chemically induced differentiation in Friend erythroleukemia cells. This study examines the effect of the macrocyclic lactone bryostatin 1 on phorbol ester responses in a Friend erythroleu kemia cell clone, PS 7. In several biological systems, bryostatin 1 was reported to mimic phorbol ester action, including activation of protein kinase C, but in 111-60 cells it blocked ...

Phorbol esters induce the human HL-60 promyelocytic cell line to differentiate along a monocytic pathway. This induction of differentiation may involve phorbol ester-induced activation of the phospholipid- and calcium-dependent protein kinase C. Bryostatin 1, a macrocyclic lactone, has been shown to compete with phorbol esters for binding to protein kinase C. We have confirmed that bryostatin 1...

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...

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...

The hallmark for protein kinase C activation is its "translocation" to membranes following generation of lipid second messengers. This translocation is mediated by the C1 and C2 domains, two membrane-targeting modules, whose engagement on membranes provides the energy for an activating conformational change in which an autoinhibitory pseudosubstrate sequence is released from the active site. No...

Tumor-promoting phorbol esters were used to manipulate the in vitro development of neural crest cells. When plated at clonal density in secondary culture, quail neural crest cells from the trunk region gave rise to three types of colonies, pigmented, unpigmented, and mixed. Pigmented colonies consisted exclusively of melanocytes; up to 50% of the unpigmented mixed colonies contained adrenergic ...

The human monocytic leukemia cell line, THP-1, shares many properties with human monocyte-derived macrophages and might be a useful model for studying foam cell formation in vitro. Therefore, we examined the ability of THP-1 cells to accumulate cholesteryl esters, the hallmark feature of foam cells, in response to culture with native low density lipoprotein (LDL), modified LDL, and platelets. T...