Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor

Newton, Alexandra C.; Brognard, John

doi:10.1016/j.tips.2017.02.002

Cited by 90 publications

(92 citation statements)

References 74 publications

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“…Consistent with the contrasting effects of individual PKC isozymes in promoting or suppressing tumor growth, it is now widely recognized that discrete members of this family can have either similar or opposite roles in a cellular context 4–6 . For example, early studies in fibroblasts showed inhibitory and promoting roles for PKCδ and PKCε, respectively, in cell growth and tumorigenesis 7 .…”

Section: Introductionmentioning

confidence: 95%

Differential Regulation of Gene Expression in Lung Cancer Cells by Diacyglycerol-Lactones and a Phorbol Ester Via Selective Activation of Protein Kinase C Isozymes

Cooke

Casado‐Medrano

Ann

et al. 2019

Sci Rep

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Despite our extensive knowledge on the biology of protein kinase C (PKC) and its involvement in disease, limited success has been attained in the generation of PKC isozyme-specific modulators acting via the C1 domain, the binding site for the lipid second messenger diacylglycerol (DAG) and the phorbol ester tumor promoters. Synthetic efforts had recently led to the identification of AJH-836, a DAG-lactone with preferential affinity for novel isozymes (nPKCs) relative to classical PKCs (cPKCs). Here, we compared the ability of AJH-836 and a prototypical phorbol ester (phorbol 12-myristate 13-acetate, PMA) to induce changes in gene expression in a lung cancer model. Gene profiling analysis using RNA-Seq revealed that PMA caused major changes in gene expression, whereas AJH-836 only induced a small subset of genes, thus providing a strong indication for a major involvement of cPKCs in their control of gene expression. MMP1 , MMP9 , and MMP10 were among the genes most prominently induced by PMA, an effect impaired by RNAi silencing of PKCα, but not PKCδ or PKCε. Comprehensive gene signature analysis and bioinformatics efforts, including functional enrichment and transcription factor binding site analyses of dysregulated genes, identified major differences in pathway activation and transcriptional networks between PMA and DAG-lactones. In addition to providing solid evidence for the differential involvement of individual PKC isozymes in the control of gene expression, our studies emphasize the importance of generating targeted C1 domain ligands capable of differentially regulating PKC isozyme-specific function in cellular models.

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Section: Introductionmentioning

confidence: 95%

Differential Regulation of Gene Expression in Lung Cancer Cells by Diacyglycerol-Lactones and a Phorbol Ester Via Selective Activation of Protein Kinase C Isozymes

Cooke

Casado‐Medrano

Ann

et al. 2019

Sci Rep

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“…PKCα represent an actionable target. PKCα inhibitors have been unsuccessful in most cancers including glioblastomas, probably because loss of function was the prevalent mechanism in these cases 26 . In the case of ChGs, the inhibition of the neomorphic PKCα D463H could open a new perspective for specific targeting of this rare subtype of glioma.…”

Section: Discussionmentioning

confidence: 99%

A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas

et al. 2018

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Chordoid glioma (ChG) is a characteristic, slow growing, and well-circumscribed diencephalic tumor, whose mutational landscape is unknown. Here we report the analysis of 16 ChG by whole-exome and RNA-sequencing. We found that 15 ChG harbor the same PRKCAD463H mutation. PRKCA encodes the Protein kinase C (PKC) isozyme alpha (PKCα) and is mutated in a wide range of human cancers. However the hot spot PRKCAD463H mutation was not described in other tumors. PRKCAD463H is strongly associated with the activation of protein translation initiation (EIF2) pathway. PKCαD463H mRNA levels are more abundant than wild-type PKCα transcripts, while PKCαD463H is less stable than the PCKαWT protein. Compared to PCKαWT, the PKCαD463H protein is depleted from the cell membrane. The PKCαD463H mutant enhances proliferation of astrocytes and tanycytes, the cells of origin of ChG. In conclusion, our study identifies the hallmark mutation for chordoid gliomas and provides mechanistic insights on ChG oncogenesis.

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“…The PKC family of kinases includes the conventional PKC isoforms (α, β, and γ) with functional C1 and C2 domains, which bind diacylglycerol (DAG) and calcium, respectively, to promote membrane translocation and activation; the novel family members (δ, ε, η, and θ) with a functional C1 domain and with a nonfunctional C2 domain; and the atypical family members (ζ and ι), which lack functional C1 and C2 domains and are primarily regulated through protein–protein interactions. Because PKCs serve as the primary receptor for phorbol esters, which are tumor promoters that enhance carcinogenesis in skin cancer models , PKCs were initially classified as tumor promoters. Similar to diacylglycerol, phorbol esters bind the C1 domain of conventional and novel PKCs.…”

Section: Challenging the Tumor‐promoting Dogma Through Systematic Evamentioning

confidence: 99%

Orange is the new black: Kinases are the new master regulators of tumor suppression

Brognard

2018

IUBMB Life

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For many decades, kinases have predominantly been characterized as oncogenes and drivers of tumorigenesis, because activating mutations in kinases occur in cancer with high frequency. The oncogenic functions of kinases relate to their roles as growth factor receptors and as critical mediators of mitogen‐activated pathways. Indeed, some of the most promising cancer therapeutic agents are kinase inhibitors. However, cancer genomics studies, especially screens that utilize high‐throughput identification of loss‐of‐function somatic mutations, are beginning to shed light on a widespread role for kinases as tumor suppressors. The initial characterization of tumor‐suppressing kinases— in particular members of the protein kinase C (PKC) family, MKK4 of the mitogen‐activated protein kinase kinase family, and DAPK3 of the death‐associated protein kinase family— laid the foundation for bioinformatic approaches that enable the identification of other tumor‐suppressing kinases. In this review, we discuss the important role that kinases play as tumor suppressors, using several examples to illustrate the history of their discovery and highlight the modern approaches that presently aid in the identification of tumor‐suppressing kinases. © 2018 IUBMB Life, 71(6):738–748, 2019

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Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor

Cited by 90 publications

References 74 publications

Differential Regulation of Gene Expression in Lung Cancer Cells by Diacyglycerol-Lactones and a Phorbol Ester Via Selective Activation of Protein Kinase C Isozymes

Differential Regulation of Gene Expression in Lung Cancer Cells by Diacyglycerol-Lactones and a Phorbol Ester Via Selective Activation of Protein Kinase C Isozymes

A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas

Orange is the new black: Kinases are the new master regulators of tumor suppression

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