Mechanism of action of the phorbol ester tumor promoters: Specific receptors for lipophilic ligands

Blumberg, Peter M.; Jaken, Susan; König, Bernhard; Sharkey, Nancy A.; Leach, Karen L.; Jeng, Arco Y.; Yeh, Erika

doi:10.1016/0006-2952(84)90448-9

Cited by 200 publications

(75 citation statements)

References 34 publications

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“…Phorbol derivatives of the 4-a! form are unable to activate PKC (Blumberg et al, 1984). We found that applications of inactive phorbol esters at concentrations IO-fold higher than those used for active phorbol esters had no effects on the currents.…”

Section: Efects Of Pkc Activators On Ca Currentsmentioning

confidence: 66%

“…Phorbol esters are exogenous plant-derived compounds that can substitute for diacylglycerol, an endogenous product of phosphatidylinositol breakdown, in activating PKC (Castagna et al, 1982;Blumberg et al, 1984;Nishizuka, 1984). We now report selective regulation of both Ca and K currents recorded under whole-cell voltage-clamp by PKC using phorbol ester and synthetic diacylglycerol (OAG) application to acutely isolated, and tissue-cultured, hippocampal neurons.…”

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confidence: 89%

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Protein kinase C activators block specific calcium and potassium current components in isolated hippocampal neurons

1988

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Whole-cell voltage-clamp techniques were used to study the effects of the protein kinase C (PKC) activators phorbol esters and OAG on Ca and K currents in differentiated neurons acutely dissociated from adult hippocampus and in tissue-cultured neurons from fetal hippocampus. PKC activators had selective depressant effects on K currents, with persistent currents (IK and IK-Ca) being reduced and transient current (IA) being unaffected. In both cell types we recorded both high-voltage- activated, noninactivating (L-type) and high-voltage-activated, rapidly inactivating (N-type) Ca current. A low-voltage-activated, rapidly inactivating (T-type) Ca current was also recorded in tissue-cultured neurons but not in acutely dissociated neurons. PKC activators markedly reduced N-type current with less effect on L-type and no effect on T- type Ca current. Effects of PKC activators could be reversed with washing or with application of PKC inhibitors H-7 or polymyxin-B, an effect that could not be attributed to inhibition of cAMP-dependent protein kinase. The Ca/calmodulin inhibitor calmidazolium was ineffective in reversing the actions of PKC activators. Using whole- cell voltage-clamp techniques, we have demonstrated that hippocampal neurons possess 3 distinguishable components of calcium current. Distinct K currents were also observed. Our data strongly support the hypothesis that both Ca and K currents are selectively regulated by PKC and that these effects occur directly on the postsynaptic neuron.

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Section: Efects Of Pkc Activators On Ca Currentsmentioning

confidence: 66%

mentioning

confidence: 89%

Protein kinase C activators block specific calcium and potassium current components in isolated hippocampal neurons

1988

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“…The divergent inhibitory and stimulatory effects of PMA were attributed to its recognised ability to activate protein kinase C (Nishizuka, 1984 That these pleiotropic responses to the phorbol compounds are due to the stimulation of the calciumactivated phospholipid-dependent protein kinase C is supported by the facts that (a) the order of potency with PMA more potent than PDBu, with 4a-phorbol and 4a-PDD inactive, was shown for all responses (Figures 1 and 3, Table 1 and text), and is the same as for activation of protein kinase C (Castagna et al, 1982), binding to phorbol ester receptors (Goodwin & Weinberg, 1982;Niedel et al, 1983) potencies (Goodwin & Weinberg, 1982;Blumberg et al, 1984); and (b) OAG had the same spectrum of action. This synthetic diacylglycerol intercalates into the membrane, thereby mimicking diacylglycerol, the endogenous substrate for protein kinase C ).…”

Section: Discussionmentioning

confidence: 70%

Divergent effects of co‐carcinogenic phorbol esters and a synthetic diacylglycerol on human neutrophil chemokinesis and granular enzyme secretion

Nourshargh

Hoult

1987

British J Pharmacology

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The effects of two co‐carcinogenic phorbol esters (phorbol myristate acetate (PMA) and phorbol dibutyrate (PDBu)) and a synthetic diacylglycerol (OAG, 1‐oleoyl‐2‐acetyl‐glycerol), which all stimulate protein kinase C, were compared with two inactive phorbol compounds (4α‐phorbol and 4α‐phorbol didecanoate (4α‐PDD)) on three functional properties of stimulated human polymorphonuclear leukocytes (PMNs): release of granular enzymes lysozyme and β‐glucuronidase, chemokinesis, and changes in cytoplasmic free calcium [Ca2+]i. PMA, PDBu and the diacylglycerol, OAG, all caused a dose‐dependent and slow (max by 15 min) release of small amounts of lysozyme with much less β‐glucuronidase and no release of cytoplasmic lactate dehydrogenase. Release was unaffected by removal of extracellular Ca2+. PMA, PDBu and OAG inhibited random movement of the cells, did not cause chemokinesis and induced a slow reduction in the basal [Ca2+]i, as measured by the quin‐2 method. PMA, PDBu and OAG increased the capacity of five independently‐acting stimulants (N‐formyl‐Met‐Leu‐Phe, leukotriene B4, C5a des‐Arg, platelet activating factor and A23187) to cause release of lysozyme and β‐glucuronidase but strongly inhibited PMN chemokinesis induced by the same five agents and reduced the stimulant‐induced increases in [Ca2+]i. PMA was always more potent than PDBu and much more potent than OAG in eliciting these stimulatory or inhibitory effects on human PMNs. In all tests, 4α‐phorbol and 4α‐PDD were inactive. The results confirm that stimulation of the diacylglycerol/protein kinase C system in human PMN, either by active phorbol esters or the synthetic diacylglycerol, causes bidirectional effects on human PMN function. In particular, activation of the C‐kinase causes inhibition of stimulated neutrophil motility, whereas the secretory functions of the cells are enhanced.

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“…It has been demonstrated that the PS/PC ratio in artificial bilayers affects the activation of protein kinase C and the insertion of protein kinase C into the bilayer [26,271. Furthermore, the fatty acid composition of the activating phospholipids has been shown to affect the activation of protein C, both the Ca*+ and phospholipid-dependent protein kinase C activity, and the effects of DAG or PMA (Snoek et al, submitted).…”

Section: Discussionmentioning

confidence: 99%

Phorbol ester binding and protein kinase C activity in normal and transformed human keratinocytes

Snoek¹,

Boonstra

Ponec

et al. 1987

Experimental Cell Research

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Normal keratinocytes, SV40-transformed keratinocytes (SVKi4), and various squamous carcinoma cell (XC) lines have been used as an in vitro model system to study the properties of phorbol ester receptor and protein kinase C expression during keratinocyte differentiation. The cell lines used exhibit a decreasing capacity to differentiate in the order of keratinocytes -SVK,,>SCC-12F2>SCC-15>SCC-4; moreover, all cell lines respond to a low external Ca*+ concentration by a decreased capacity to differentiate. Normal keratinocytes exhibited the highest number of phorbol ester receptors as compared to the other cell lines, while each individual cell line exhibited a higher number of phorbol ester receptors during growth under normal Ca*+ conditions as compared to cells grown under low Ca*+ conditions. The apparent dissociation constant (Kd) demonstrated only small variations in the various cell lines. In contrast, the cytoplasmic protein kinase C activity, was found to be higher in cells grown under low Ca*' conditions than in cells grown under normal Ca2+ conditions, indicating the absence of a causal relationship between cytoplasmic protein kinase C activity and phorbol ester receptor expression. Therefore the properties of protein kinase C have been determined in more detail in normal keratinocytes and SCC-15 cells. These studies revealed differences between protein kinase C properties from the two cell lines grown under normal and low Ca*+ conditions. The differences included the effect of phorbol 12-myristate 13-acetate (PMA) on the redistribution pattern of protein kinase C between the cytoplasmic and particulate fractions as well as the activating effect of diolein in vitro on protein kinase C activity, partly purified from particulate or cytoplasmic fractions. These observations demonstrate that the functional protein kinase C activity of keratinocytes is determined by various endogenous and exogenous activators and that these activators are modulated differently in various cell lines, under various growth conditions (low Ca*+ versus normal Ca2+). 0 1987 Academic Press, Inc.Mouse skin has been a main tool in the investigation of the tumor promoting activity of, in particular, the phorbol esters during multiple-stage carcinogenesis [l]. In addition to being well known as tumor promoters, these plant-derived cyclic diterpene compounds are known to modulate cellular differentiation and/or proliferation in a variety of cells and tissues (reviewed in [2]). The effects of phorbol esters on cellular differentiation are of particular interest since the regulation of cellular differentiation may be more important than the control of proliferation during the development of neoplasia. In skin, in contrast to many other tissues or organs, all three effects of phorbol esters have been demonstrated: tumor promotion, induction of terminal differentiation, and stimulation of cellular proliferation [3-51. A heterogeneous response is observed often in kera-' To whom reprint requests should be sent at

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Mechanism of action of the phorbol ester tumor promoters: Specific receptors for lipophilic ligands

Cited by 200 publications

References 34 publications

Protein kinase C activators block specific calcium and potassium current components in isolated hippocampal neurons

Protein kinase C activators block specific calcium and potassium current components in isolated hippocampal neurons

Divergent effects of co‐carcinogenic phorbol esters and a synthetic diacylglycerol on human neutrophil chemokinesis and granular enzyme secretion

Phorbol ester binding and protein kinase C activity in normal and transformed human keratinocytes

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