Tumor-promoting 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. 

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... 

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. 

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. 

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... 

Montesano R, Orci L (1985) Tumor-promoting phorbol esters induce angiogenesis in vitro. Cell 42 469 77... 

Roger, P.P., Reuse, S., Servais, P., Van Heuverswyn, B., Dumont, J.E., 1986, Stimulation of cell proliferation and inhibition of differentiation expression by tumor-promoting phorbol esters in dog thyroid cells in primary culture. Cancer Res. 46 898. 

Miyagi, T, Sagawa, J., Kuroki, T, Matsuya, Y, and Tsuiki, S., 1990d, Tumor-promoting phorbol ester induced alterations of sialidases and sialyltransferase activities of JB6 cells, Jpn. J. Cancer Res. 81 1286-1292. 

---