Tumor-promoting phorbol

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. 

Ahmed S, Lee J, Kozma R, Best A, Monfries C, Lim LA (1993) A novel functional target for tumor-promoting phorbol esters and lysophosphatidic acid. The p21rac-GTPase activating protein n-chimaerin. J Biol Chem 268 10709-10712... 

Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y (1982) Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 257 7847-7851... 

PKC is a serine/threonine protein kinase comprised of at least 11 isozymic forms (Nishizuka 1995 Liu and Heckman 1998). These isozymic forms have been classified as atypical, classical, and novel. Classical PKCs (a, pi, pH, and y) are activated by Ca2+, DAG, phosphatidylserine (PS), and the tumor promoter phorbol 12-myristate 13-acetate (PMA). Novel PKCs (6, e, r, i, and 0) are activated by DAG, PS, and unsaturated fatty acids, while atypical PKCs (C, A, and 0 are insensitive to DAG but are activated by PS and phosphatidylinositides (reviewed in Liu and Heckman 1998 Newton and Johnson 1998 Nakanishi et al. 1993). PKCs have been implicated in a wide variety of cellular responses, including growth, differentiation, gene expression, angiogenesis, contractility, and vesicle trafficking (Nishizuka 1995). 

Glucagon markedly potentiates the hepatic actions of other Ca2+-mobilizing hormones, e.g., vasopressin and epinephrine. This can be attributed to increased IP3 production and Ca2+ mobilization, and also to the opening of more plasma membrane Ca2+ channels. On the other hand, the actions of glucagon and other Ca2+-mobilizing hormones on liver cell Ca2+ fluxes are inhibited or abolished by tumor promoting phorbol esters. There is evidence that this inhibition is exerted at the level of Gp or on another factor involved in the control of PIP2 phospholipase C and may involve protein kinase C. 

Does defective lysosomal catabolism in I-cell disease somehow feed back to affect the expression of lysosomal proteins and their receptors Compared with control fibroblasts, twofold increases in man-6-P/IGF-II receptors have been observed for fibroblasts from patients with I-cell disease. This increase in receptor concentration stems from an increased rate of synthesis, not from differences of receptor stability. Interestingly, when they are exposed to insulinlike growth factors I and II or tumor-promoting phorbol esters, I-cell fibroblasts respond differently from control fibroblasts. These observations indicate multiple regulatory sites in the man-6-P/IGF-II receptor pathway. 

Human neutrophils were exposed to the tumor promoter phorbol myristate acetate (PMA, 100 nM). After a steady state of metabolism had been achieved, the cell suspension was homogenized and, after centrifugation, membrane and supernatant fractions were collected. Membrane and supernatant fractions were also prepared from cells that had not been exposed to PMA. Samples of both homogenates (i.e., prior to centrifugation) were also collected. The fractions were then assayed for the presence of protein kinase C. After the protein kinase C assay was performed the following data were obtained ... 

The oil of Croton tiglium (croton) has a violent purgative action and contains tumor-promoting phorbol diesters and triesters. 

Ohuchi, K., Watanabe, M., Hirasawa, N., Yoshizaki, S., Mue, S. and Tsurufuji, S. (1990). Suppression by adrenoceptor 0-agonists of vascular permeability increase and edema formation induced by arachidonate metabolites, plateletactivating factor, and tumor-promoting phorbol ester TPA. Immunopharmacology 20, 81-88. 

Birnboim, H.C. (1982). DNA strand breakage in human leukocytes exposed to tumor promoter, phorbol myristate acetate. Science, 215, 1247-1249. 

Olsnes S, Carvajal E, Sandvig K (1986) Interactions between diphtheria toxin entry and anion transport in Vero cells. III. Effect on toxin binding and anion transport of tumor-promoting phorbol esters, vanadate, fluoride and salicylate. J Biol Chem 261 1562-1569. 

Marnett LJ and Ji C (1994) Modulation of oxidant formation in mouse skin in vivo by tumor-promoting phorbol esters. Cancer Research 54 1886s-1889s. 

As cellular activation induces viral expression, and causes the former latent viruses to become exposed to HAART therapy, several efforts have been made to activate in vivo the silent proviruses by activating the resting CD4 T cells. However, the adverse effects and poor clinical benefit found indicate that this approach is not of value [147, 148]. Prostratine and DPP are not tumor-promoting phorbol esters, but are under examination because they can activate the provirus without complete activation of the cell [149, 150]. However, the elimination of cells infected with latent proviruses is not yet sufficiently efficient, and much needs to be done to address the... 

Tumor Promoter Phorbol-Myristate-Acetate Induces a Prooxidant State which Causes the Accumulation of Poly(ADP-Rihose) in Fibroblasts... 

Tumor Promoter Phorbol-Myristate-Acetate Induces a Prooxidant State... 

T. (1982). Tumor promoter phorbol T cell dependent inducer of immuno-Clin. Immuno. Im-... 

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