Key Points
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Protein kinase C (PKC) is a family of serine/threonine kinases that regulates a diverse set of cellular processes including proliferation, apoptosis, cell survival and migration, and there is a substantial amount of evidence linking PKC to tumorigenesis. Studying PKC regulation of these processes and how misregulation might contribute to tumorigenesis is complicated by the fact that each individual PKC isozyme has a distinct role in these processes in a cell-type-dependent manner.
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There is a limited number of instances in which mutation of PKCs in humans is linked to a cancer phenotype; however, altered levels of PKC isoforms can be found in many types of human cancers. In many cases, altered expression of PKC can also be linked to disease progression.
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PKCs were originally thought to be pro-mitogenic kinases, but this effect seems to be PKC-isozyme-dependent and cell-type-dependent, as many PKCs can also inhibit cell-cycle progression. Several PKCs have been shown to be anti-proliferative in various cell types, generally through upregulation of cell-cycle inhibitors.
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PKCε promotes cell survival in many cell types through increased activation of the Akt pathway and upregulation of pro-survival factors. Furthermore, PKCε overexpression has been linked to chemotherapeutic resistance in various cell types.
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PKCδ is generally considered a growth inhibitory or pro-apoptotic PKC, and many types of apoptotic stimuli can induce PKCδ translocation to mitochondria, leading to cytochrome c release, caspase-3 cleavage and generation of a constitutively active PKCδ catalytic fragment that is important for phosphorylation of nuclear PKC substrates. Activation of PKCδ can also trigger the autocrine secretion of death factors and kill cells through the activation of the extrinsic apoptotic pathway.
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Several PKCs have been implicated in invasion and metastasis of cancer cells; however, knowledge of the molecular mechanisms through which PKC might contribute to these processes is still vague.
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Emerging evidence indicates that PKC, specifically PKCβII, might be an important mediator of vascular endothelial growth factor (VEGF)-induced angiogenesis and have a role in VEGF-induced endothelial-cell proliferation.
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Several other classes of proteins can be activated by phorbol esters or DAG, including protein kinase D, Ras guanyl nucleotide-releasing proteins, chimaerins, diacylglycerol kinases and Munc13s. Several of these proteins have also been implicated in cancer progression.
Abstract
Almost three decades after the discovery of protein kinase C (PKC), we still have only a partial understanding of how this family of serine/threonine kinases is involved in tumour promotion. PKC isozymes — effectors of diacylglycerol (DAG) and the main targets of phorbol-ester tumour promoters — have important roles in cell-cycle regulation, cellular survival, malignant transformation and apoptosis. How do PKC isozymes regulate these diverse cellular processes and what are their contributions to carcinogenesis? Moreover, what is the contribution of all phorbol-ester effectors, which include PKCs and small G-protein regulators? We now face the challenge of dissecting the relative contribution of each DAG signal to cancer progression.
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The Kazanietz laboratory is funded by grants from the US National Institutes of Health and Department of Defense.
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Glossary
- ApcMin/+ mouse
-
A mouse strain harbouring a nonsense mutation at codon 850 in one allele of the Apc (adenomatous polyposis coli) gene. Animals develop multiple intestinal adenomas at an early age.
- Mitochondrial-dependent apoptosis
-
A programmed cell death, generally triggered by stress, which is initiated by loss of mitochondrial integrity and a concomitant release of mitochondrial proteins such as cytochrome c.
- Vascular gene-trap screen
-
A screen for proteins that are expressed in developing vascular cells using random insertion of a gene-trap reporter vector into intronic regions of the genomic DNA of embryonic stem cells.
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Griner, E., Kazanietz, M. Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 7, 281–294 (2007). https://doi.org/10.1038/nrc2110
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DOI: https://doi.org/10.1038/nrc2110
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