Diacylglycerol Signaling

Chapter 3
Phorbol Esters and Diacylglycerol:
The PKC Activators
Peter M. Blumberg, Noemi Kedei, Nancy E. Lewin, Dazhi Yang,
Juan Tao, Andrea Telek, and Tamas Geczy
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.
Keywords C1 domain • Diacylglycerol • Phorbol ester • Protein kinase C
Abbreviations
GFP Green fluorescent protein
PDBu Phorbol 12,13-dibutyrate
PKC Protein kinase C
PMA Phorbol 12-myristate 13-acetate
P.M. Blumberg (*), N. Kedei, N.E. Lewin, D. Yang, J. Tao, A. Telek, and T. Geczy
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
e-mail: blumberp@dc37a.nci.nih.gov
M.G. Kazanietz (ed.), Protein Kinase C in Cancer Signaling and Therapy,
Current Cancer Research, DOI 10.1007/978-1-60761-543-9_3,
© Springer Science+Business Media, LLC 2010
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