Phorbol ester

The spatial and steric requirements for high affinity binding to protein kinase C (PKC), a macromolecule that has not yet been crystallized, were determined. Protein kinase C plays a critical role in cellular signal transduction and is in part responsible for cell differentiation. PKC was identified as the macromolecular target for the potent tumor-promoting phorbol esters (25). The natural agonists for PKC are diacylglycerols (DAG) (26). The arrows denote possible sites of interaction. 

PKC isozymes are involved in a wide array of diverse cellular functions [5]. Most isozymes (e.g., PKC (3) are involved in proliferative responses, and hyperactivation with phorbol esters most typically results in cell growth and differentiation. However, isozymes can have opposing functions. PKC 8 is well-characterized as an apoptotic kinase, whereas the closely related PKC e is antiapoptotic. PKC also plays a key role in learning and memory. 

Conventional and novel PKC isozymes are potently activated by phorbol esters, heterocyclic compounds found in the milky sap exuded by plants of the Euphorbiaccae family. This sap was used medicinally as a counterirritant and cathartic agent over the millennia we now know that the active ingredients, phorbol esters, specifically bind to the Cl domain, the diacylglycerol sensor described above. In fact, their ability to recruit PKC to membranes is so effective that phorbol esters cause maximal activation of conventional PKCs, bypassing the requirement for Ca2+. This module is found in a number of other proteins in addition to PKC, so the profound effects of phorbol esters on cells are mediated by other proteins in addition to PKC. 

Bryostatins are another class of compounds that bind to the Cl domain and result in acute activation of PKC. However, unlike phorbol esters, these marine natural products have antitumor effects. Bryostatins are currently in phase II clinical trials and show promise as anticancer drugs, particularly when combined with other adjuvant therapy. 

Diacylglycerol Phorbol Esters Protein Kinase C Phospholipases... 

Just as myosins are able to move along microfilaments, there are motor proteins that move along microtubules. Microtubules, like microfilaments, are polar polymeric assemblies, but unlike actin-myosin interactions, microtubule-based motors exist that move along microtubules in either direction. A constant traffic of vesicles and organelles is visible in cultured cells especially using time-lapse photography. The larger part of this movement takes place on micrombules and is stimulated by phorbol ester (an activator of protein kinase C), and over-expression of N-J aj oncoprotein (Alexandrova et al., 1993). 

DAG is a potent activator of protein kinase C (PKC). It has been long known that ACh causes an increase in the number of effective L-channels in many smooth muscle cells. This effect is mimicked by phorbol esters (known to activate PKC) and DAG itself Therefore, it has been suggested that one of the actions of ACh involves the activation of L-channels via the evoked increase of DAG. 

By interfering with any one of the many phases associated with these second messenger pathways, toxins may alter channel gating. For example, the blue green algal toxins, aplysiatoxin, and lyngbyatoxin bind to and activate protein kinase C in a manner similar to phorbol esters (73). They also stimulate arachidonic acid metabolism (74). The coral toxin, palytoxin, also stimulates arachidonic acid breakdown albeit by an unknown mechanism (74) and affects other biochemical activities of the cell (see chapters by Fujiki et al., Wattenberg et al., and Levine et al., this volume). 

Palytoxin is a relatively large (MW 2681), hydrophilic compound (7, 2), unlike the prototypical TPA-type tumor promoters, the phorbol esters. Although palytoxin... 

In contrast to the TPA-type tumor promoters, palytoxin, thapsigargin, and okadaic acid are classified as non-TPA type tumor promoters, which do not bind to phorbol ester receptors, or activate protein kinase C in vitro (Table II) (6,25-27). In this chapter, thapsigargin is not discussed, because it is derived from terrestrial plants. 

Signoret N, Oldridge J, Pelchen-Matthews A, Klasse PJ, Tran T, Brass LF, Rosenkilde MM, Schwartz TW, Holmes W, Dallas W, Luther MA, Wells TN, Hoxie JA, Marsh M (1997) Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4. J Cell Biol 139 651-664... 

Ml and M3 receptors mediate the excitatory effects and since this postspike hyperpolarisation is blocked by phorbol esters and is therefore presumably dependent on IP3 production, one would expect it to be mediated through M] receptors (see above), especially as these are located postsynaptically. Unfortunately it does not appear to be affected by pirenzapine, the Mi antagonist. By contrast, muscarinic inhibition of the M current is reduced by the Mi antagonist but as it is not affected by phorbol esters is not likely to be linked to IP3 production, an Mi effect. 

ROY s, SEN c K, KOBUCHi H and PACKER L (1998) Antioxidant regnlation of phorbol ester-indnced adhesion of hiunan Jurkat T-cells to endothehal cells Free Radical Biology and Medicine 25, 229—41. 

KATiYAR s K and MUKHTAR H (1997) Inhibition of phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate-caused inflammatory responses in SENCAR mouse skin by black tea polyphenols . Carcinogenesis, 18 1911-16. 

Ireson, C. et al.. Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production. Cancer Res., 61, 1058, 2001. 

Abundance of Na /H exchanger transcripts in vascular smooth muscle and HL60 cells is increased by serum, phorbol esters, fibroblast growth factor and platelet-derived growth factor [78,79]. The increase in NHE-1 mRNA levels in PMA-treated HL60 cells is due to increased gene transcription. 

Kensler, T.W. and Trush, M.A, (1983). Inhibition of oxygen radical metabolism in phorbol ester-activated polymorphonuclear leukocytes by an antitumor promoting copper complex with superoxide dismutase-mimetic activity. Biochem. Pharmacol. 32, 3485-3487. 

Ludwig A, Hundhausen C, Lambert MH, et al. Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM 10 and ADAM 17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb Chem High Throughput Screen 2005 8 161-171. 

Thomas, S. M., DeMarco, M., D Arcangelo, G., Halegoua, S., and Brugge, J. S. (1992). Ras is essential for nerve growth factor- and phorbol ester-induced tyrosine phosphorylation of MAP kinases. Cell 68 1031-1040. 

The majority of these members are a receptor for phorbol esters, the tumor-promoting products obtained from croton oil. One of them, 12-O-tctradccanoylphorbol- 13-acetate (TPA), is a potent... 

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