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Phorbol Esters and Diacylglycerol: The PKC Activators

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Book cover Protein Kinase C in Cancer Signaling and Therapy

Part of the book series: Current Cancer Research ((CUCR))

Abstract

Protein kinase C (PKC) represents the most prominent of the families of signaling proteins integrating response to the ubiquitous lipophilic second messenger sn-1,2-diacylglycerol and to its ultrapotent analogs, the tumor-promoting phorbol esters. Response is mediated through twin conserved zinc finger structures, the C1 domains. The C1 domains function as hydrophobic switches, for which ligand binding completes a hydrophobic surface on the face of the C1 domain, driving membrane association of PKC and enzymatic activation. Since the lipid bilayer provides critical contacts for ligand binding, along with the C1 domain, membrane heterogeneity provides an important mechanism for diversity, as do the differential functions of the twin C1 domains. Consistent with such mechanistic diversity, PKC ligands can differ dramatically in biological consequences. Thus, whereas PKC ligands have provided the paradigm for tumor promoters, some PKC ligands in fact function as inhibitors of tumor promotion. Reflecting the central role of PKC in cellular signaling, PKC has emerged as a promising therapeutic target for cancer with several PKC ligands currently in clinical trials.

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Abbreviations

GFP:

Green fluorescent protein

PDBu:

Phorbol 12,13-dibutyrate

PKC:

Protein kinase C

PMA:

Phorbol 12-myristate 13-acetate

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Acknowledgments

This contribution was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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  1. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Room 4048, 37 Convent Drive MSC 4255, Bethesda, MD, 20892-4255, USA

    Peter M. Blumberg, Noemi Kedei, Nancy E. Lewin, Dazhi Yang, Juan Tao, Andrea Telek & Tamas Geczy

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Correspondence to Peter M. Blumberg .

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    Marcelo G. Kazanietz

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Blumberg, P.M. et al. (2010). Phorbol Esters and Diacylglycerol: The PKC Activators. In: Kazanietz, M. (eds) Protein Kinase C in Cancer Signaling and Therapy. Current Cancer Research. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-543-9_3

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