-
Mechanism of action of the phorbol ester tumor promoters: specific receptors for lipophilic ligands.Biochemical Pharmacology Mar 1984Cells and tissue preparations specifically bind the phorbol ester tumor promoters. The agreement in structure-activity relationships between binding and biological...
Cells and tissue preparations specifically bind the phorbol ester tumor promoters. The agreement in structure-activity relationships between binding and biological response strongly argues that these binding sites function as phorbol ester receptors. Upon subcellular fractionation, the phorbol ester binding activity is particulate. In addition, a phorbol ester apo-receptor can be detected in cytosol which requires phospholipids for reconstitution. This apo-receptor appears to correspond to protein kinase C. Diacylglycerols, the probable natural activators of protein kinase C, competitively inhibit phorbol ester binding, consistent with their being the postulated endogenous phorbol ester analogs. In certain systems, heterogeneity of phorbol ester binding is found. An outstanding issue therefore is whether protein kinase C is the phorbol ester receptor or whether it is only the most abundant class of receptor. Although this question remains unresolved, we can demonstrate heterogeneity of phorbol ester binding by reconstitution of apo-receptor into a heterogeneous lipid environment.
Topics: Animals; Brain Chemistry; Caenorhabditis elegans Proteins; Calcium; Carrier Proteins; Diglycerides; Humans; Neoplasms; Phorbol 12,13-Dibutyrate; Phorbol Esters; Phorbols; Phospholipids; Protein Kinase C; Protein Kinases; Receptors, Cell Surface; Receptors, Drug; Tritium
PubMed: 6324806
DOI: 10.1016/0006-2952(84)90448-9 -
Brain Research Dec 1996The action of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), the potent stimulator of protein kinase C (PKC), on acetylcholine-activated currents (I(Ach))...
The action of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), the potent stimulator of protein kinase C (PKC), on acetylcholine-activated currents (I(Ach)) was investigated in voltage clamped Xenopus laevis oocytes injected with RNAs encoding murine embryonic nicotinic acetylcholine receptor (AChR) subunits. Comparable potentiation and acceleration of decay of I(ACh) were observed within minutes of phorbol ester application in oocytes injected with various RNA subunit combinations: (i) alpha beta gamma delta; (ii) alpha beta gamma; (iii) alpha beta delta; and (iv) alpha beta gamma delta(AAA), a mutant of the delta subunit with serine residues 360-361-362 mutated to alanine. Our findings indicate that the effects on I(ACh) induced by PKC stimulation are independent of both gamma and delta subunits and, accordingly, of the presence of PKC phosphorylation sites on delta subunit. It is here suggested a novel PKC-dependent modulatory mechanism of cholinergic receptor which does not involve direct phosphorylation of the AChR and requires phosphorylation of intermediate regulatory protein(s).
Topics: Animals; Mutation; Oocytes; Phorbol Esters; Receptors, Nicotinic; Xenopus
PubMed: 9117392
DOI: 10.1016/s0006-8993(96)00961-4 -
The Journal of Biological Chemistry May 2001The novel phorbol ester receptor beta2-chimaerin is a Rac-GAP protein possessing a single copy of the C1 domain, a 50-amino acid motif initially identified in protein...
The novel phorbol ester receptor beta2-chimaerin is a Rac-GAP protein possessing a single copy of the C1 domain, a 50-amino acid motif initially identified in protein kinase C (PKC) isozymes that is involved in phorbol ester and diacylglycerol binding. We have previously shown that, like PKCs, beta2-chimaerin binds phorbol esters with high affinity in a phospholipid-dependent manner (Caloca, M. J., Fernandez, M. N., Lewin, N. E., Ching, D., Modali, R., Blumberg, P. M., and Kazanietz, M. G. (1997) J. Biol. Chem. 272, 26488-26496). In this paper we report that like PKC isozymes, beta2-chimaerin is translocated by phorbol esters from the cytosolic to particulate fraction. Phorbol esters also induce translocation of alpha1 (n)- and beta1-chimaerins, suggesting common regulatory mechanisms for all chimaerin isoforms. The subcellular redistribution of beta2-chimaerin by phorbol esters is entirely dependent on the C1 domain, as revealed by deletional analysis and site-directed mutagenesis. Interestingly, beta2-chimaerin translocates to the Golgi apparatus after phorbol ester treatment, as revealed by co-staining with the Golgi marker BODIPY-TR-ceramide. Structure relationship analysis of translocation using a series of PKC ligands revealed substantial differences between translocation of beta2-chimaerin and PKCalpha. Strikingly, the mezerein analog thymeleatoxin is not able to translocate beta2-chimaerin, although it very efficiently translocates PKCalpha. Phorbol esters also promote the association of beta2-chimaerin with Rac in cells. These data suggest that chimaerins can be positionally regulated by phorbol esters and that each phorbol ester receptor class has distinct pharmacological properties and targeting mechanisms. The identification of selective ligands for each phorbol ester receptor class represents an important step in dissecting their specific cellular functions.
Topics: Animals; COS Cells; Caenorhabditis elegans Proteins; Carrier Proteins; Isoenzymes; Neoplasm Proteins; Phorbol Esters; Protein Kinase C; Receptors, Drug; Signal Transduction
PubMed: 11278894
DOI: 10.1074/jbc.M011368200 -
The Journal of Investigative Dermatology Dec 1986In earlier studies, it was shown that the human plasma-spreading glycoprotein, epibolin (the 65 kD species of serum-spreading factor or vitronectin), requires a second...
In earlier studies, it was shown that the human plasma-spreading glycoprotein, epibolin (the 65 kD species of serum-spreading factor or vitronectin), requires a second plasma component, termed coepibolin, in order to support maximal dissociated epidermal cell spreading in tissue culture. Whereas epibolin alone in defined medium supports some cell spreading, the purified plasma coepibolin preparations do not effect spreading in the absence of epibolin. Although not yet entirely purified, coepibolin associates with some plasma fractions but not with others; it is certainly not a property of all proteins, e.g., while bovine serum albumin (BSA) has coepibolin activity, ovalbumin does not. The data presented here show that the phorbol ester, 12-tetra-decanoyl-1-phorbol-13-acetate (TPA) can act as a potent coepibolin and support maximal spreading over a concentration range of 10-100 ng/ml. In the absence of epibolin TPA does not stimulate the spreading of epidermal cells when given alone or in the presence of BSA or ovalbumin. Coepibolin activity appears to associate with tumor-promoting activity in that the phorbol derivative, phorbol-12,13-didecanoate, shows coepibolin activity, while its inactive non-tumor-promoting isomer, phorbol-4 alpha-phorbol-12,13-didecanoate, does not. These data suggest that the proteinaceous plasma-derived cofactor acts in a fashion similar to TPA and that this as yet unexplained mechanism of TPA action is important to the full expression of epibolin and to the early phase of epidermal cell spreading.
Topics: Animals; Diglycerides; Epidermal Cells; Glycoproteins; Guinea Pigs; Ovalbumin; Phorbol Esters; Serum Albumin; Tetradecanoylphorbol Acetate; Vitronectin
PubMed: 2431072
DOI: 10.1111/1523-1747.ep12456946 -
Mutation Research Dec 1995A novel serine/threonine protein kinase regulated by phorbol esters and diacylglycerol (named PKD) has been identified. PKD contains a cysteine-rich repeat sequence... (Review)
Review
A novel serine/threonine protein kinase regulated by phorbol esters and diacylglycerol (named PKD) has been identified. PKD contains a cysteine-rich repeat sequence homologous to that seen in the regulatory domain of protein kinase C (PKC). A bacterially expressed NH2-terminal domain of PKD exhibited high affinity phorbol ester binding activity (Kd = 35 nM). Expression of PKD cDNA in COS cells conferred increased phorbol ester binding to intact cells. The catalytic domain of PKD contains all characteristic sequence motifs of serine protein kinases but shows only a low degree of sequence similarity to PKCs. The bacterially expressed catalytic domain of PKD efficiently phosphorylated the exogenous peptide substrate syntide-2 in serine but did not catalyse significant phosphorylation of a variety of other substrates utilised by PKCs and other major second messenger regulated kinases. PKD expressed in COS cells showed syntide-2 kinase activity that was stimulated by phorbol esters in the presence of phospholipids. We propose that PKD may be a novel component in the transduction of diacylglycerol and phorbol ester signals.
Topics: Amino Acid Sequence; Animals; Diglycerides; Humans; Molecular Sequence Data; Phorbol 12,13-Dibutyrate; Phorbol Esters; Protein Kinase C; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 8538623
DOI: 10.1016/0027-5107(95)00141-7 -
FEBS Letters Oct 1998Protein kinase D (PKD) is a serine/threonine kinase that binds phorbol esters in a phospholipid-dependent manner via a tandemly repeated cysteine-rich, zinc finger-like...
Protein kinase D (PKD) is a serine/threonine kinase that binds phorbol esters in a phospholipid-dependent manner via a tandemly repeated cysteine-rich, zinc finger-like motif (the cysteine-rich domain, CRD). Here, we examined whether the individual cysteine-rich motifs of the CRD of PKD (referred to as cysl and cys2) are functionally equivalent in mediating phorbol ester binding both in vivo and in vitro. Our results demonstrate that the cysl and cys2 motifs of the CRD of PKD are functionally dissimilar, with the cys2 motif responsible for the majority of [3H]phorbol 12,13-dibutyrate (PDB) binding, both in vivo and in vitro.
Topics: Animals; COS Cells; Cysteine; Glutathione Transferase; Mutagenesis, Site-Directed; Phorbol 12,13-Dibutyrate; Phorbol Esters; Protein Kinase C; Recombinant Proteins; Transfection
PubMed: 9804164
DOI: 10.1016/s0014-5793(98)01189-2 -
Journal of Cosmetic Dermatology Jun 2016Soap is the most useful things which we use our everyday life in various cleansing and cosmetics purposes. Jatropha oil is nonedible oil which has more benefits to soap... (Review)
Review
Soap is the most useful things which we use our everyday life in various cleansing and cosmetics purposes. Jatropha oil is nonedible oil which has more benefits to soap making. It has also cosmetics and medicinal properties. But the presence of toxic Phorbol esters in Jatropha oil is the main constrains to use it. So it is necessary to search a more suitable method for detoxifying the Jatropha oil before the use as the main ingredient of soap production. This review implies a more suitable method for removing phorbol esters from Jatropha oil. Several parameters such as the % yield of pure Jatropha oil soap, TFM value of soap, total alkali content, free caustic alkalinity content, pH, the antimicrobial activity, and CMC value of general soap should be taken into consideration for soap from detoxified Jatropha oil.
Topics: Cosmetics; Humans; Jatropha; Malaysia; Materials Testing; Phorbol Esters; Phytotherapy; Plant Oils; Quality Control; Soaps
PubMed: 26777540
DOI: 10.1111/jocd.12209 -
Cancer Letters Apr 1984Gap junctions are known to mediate cell to cell coupling. This study shows that the potent tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), drastically... (Comparative Study)
Comparative Study
Gap junctions are known to mediate cell to cell coupling. This study shows that the potent tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), drastically affects the presence of gap junctions between mouse interfollicular epidermal (IFE) cells. In a time course ultrastructural study after a single application of 1 microgram of TPA the gap junctions between the IFE basal cells begin to decrease by 10 h post-exposure, are totally absent between 18 h and 30 h, and start reappearing at 30 h after TPA application. The potent hyperplasiogen , but very weak tumor promoter, mezerein, produces comparable hyperplasia and wide intercellular spaces but the population of gap junctions remains unchanged.
Topics: Animals; Cell Communication; Diterpenes; Female; Intercellular Junctions; Mice; Phorbol Esters; Phorbols; Skin; Terpenes; Tetradecanoylphorbol Acetate; Time Factors
PubMed: 6713375
DOI: 10.1016/0304-3835(84)90173-3 -
Neuron Jul 1998Munc13-1, a mammalian homolog of C. elegans unc-13p, is thought to be involved in the regulation of synaptic transmission. We now demonstrate that Munc13-1 is a...
Munc13-1, a mammalian homolog of C. elegans unc-13p, is thought to be involved in the regulation of synaptic transmission. We now demonstrate that Munc13-1 is a presynaptic high-affinity phorbol ester and diacylglycerol receptor with ligand affinities similar to those of protein kinase C. Munc13-1 associates with the plasma membrane in response to phorbol ester binding and acts as a phorbol ester-dependent enhancer of transmitter release when overexpressed presynaptically in the Xenopus neuromuscular junction. These observations establish Munc13-1 as a novel presynaptic target of the diacylglycerol second messenger pathway that acts in parallel with protein kinase C to regulate neurotransmitter secretion.
Topics: Amino Acid Sequence; Animals; Biological Transport; Brain; Caenorhabditis elegans Proteins; Carrier Proteins; Cell Line; Female; Humans; Molecular Sequence Data; Nerve Tissue Proteins; Neuromuscular Junction; Neurotransmitter Agents; Phorbol Esters; Presynaptic Terminals; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Drug; Synaptic Transmission; Tissue Distribution; Xenopus
PubMed: 9697857
DOI: 10.1016/s0896-6273(00)80520-6 -
Journal of Neurophysiology Oct 19921. The electrophysiological properties of the sensory neurons that mediate withdrawal reflexes in Aplysia are modulated by a number of second messengers. For example,...
1. The electrophysiological properties of the sensory neurons that mediate withdrawal reflexes in Aplysia are modulated by a number of second messengers. For example, the second messengers adenosine 3',5'-cyclic monophosphate (cAMP) and arachidonic acid modulate the S-K+ current (IK,S) and the calcium-activated K+ current (IK,Ca). Recent evidence suggests that protein kinase C (PKC) may also be an important regulator of cellular plasticity. In the present study we examined the possibility that IK,Ca was modulated by the activation of PKC in the pleural sensory neurons. 2. In voltage-clamped sensory neurons the application of phorbol esters, such as phorbol dibutyrate (PDBu), phorbol myristate (PMA), and phorbol diacetate (PDAc), which activate PKC, caused a dose-dependent increase in a voltage-dependent current with properties that resembled IK,Ca. The inactive isomer of phorbol ester, 4 alpha-phorbol, was without effect. 3. This phorbol ester-sensitive current had the kinetics and pharmacological sensitivity of IK,Ca. The current developed slowly during step depolarizations, showed little inactivation, and was activated at membrane potentials greater than approximately 0 mV. In addition, the current modulated by phorbol esters was blocked by a concentration of tetraethylammonium (TEA) that blocks a component of IK,Ca in the sensory neurons. 4. IK,Ca, which was activated directly by the iontophoretic injection of Ca2+, was also enhanced by PDBu. Moreover, the enhancement of Ca(2+)-elicited responses by PDBu persisted after Ca2+ influx was blocked by cobalt. These results indicate that at least one component of the modulation of IK,Ca by PDBu was independent of the modulation of voltage-dependent Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Aplysia; Calcium; Dose-Response Relationship, Drug; Enzyme Activation; Ganglia; In Vitro Techniques; Isoquinolines; Kinetics; Membrane Potentials; Neurons, Afferent; Phorbol 12,13-Dibutyrate; Phorbol Esters; Phorbols; Piperazines; Potassium Channels; Protein Kinase C; Protein Kinase Inhibitors; Second Messenger Systems; Tetradecanoylphorbol Acetate; Tetraethylammonium; Tetraethylammonium Compounds
PubMed: 1432069
DOI: 10.1152/jn.1992.68.4.1079