Abstract
Protein kinase C (PKC) isozymes are key signal transducers involved in normal physiology and disease and have been widely implicated in cancer progression. Despite our extensive knowledge of the signaling pathways regulated by PKC isozymes and their effectors, there is essentially no information on how individual members of the PKC family regulate gene transcription. Here, we report the first PKC isozyme-specific analysis of global gene expression by microarray using RNAi depletion of diacylglycerol/phorbol ester-regulated PKCs. A thorough analysis of this microarray data revealed unique patterns of gene expression controlled by PKCα, PKCδ, and PKCε, which are remarkably different in cells growing in serum or in response to phorbol ester stimulation. PKCδ is the most relevant isoform in controlling the induction of genes by phorbol ester stimulation, whereas PKCε predominantly regulates gene expression in serum. We also established that two PKCδ-regulated genes, FOSL1 and BCL2A1, mediate the apoptotic effect of phorbol esters or the chemotherapeutic agent etoposide in prostate cancer cells. Our studies offer a unique opportunity for establishing novel transcriptional effectors for PKC isozymes and may have significant functional and therapeutic implications.
Highlights
Very recent studies revealed that Protein kinase C (PKC)␦ and PKC⑀ have opposite roles in the secretion of TNF␣, a death factor implicated in prostate cancer cell apoptosis, and distinctively modulate cell death induced by this cytokine in prostate cancer cells [6, 12, 14, 15]
Despite a few reports of genes differentially regulated by PKC isozymes, such as GM-CSF, NOX4, and IL-8 [22,23,24], there is essentially no information regarding the ability of individual members of the PKC family to regulate gene expression in a global manner
Did we establish unique patterns of gene expression controlled by individual PKCs, but we identified novel PKC␦-specific regulated genes implicated in LNCaP cell death
Summary
2 To whom correspondence should be addressed: 421 Curie Blvd., 1256 BRB the nPKC classes respond to the receptor-generated lipid second messenger diacylglycerol (DAG) or DAG mimetics, such as the phorbol esters, an event that occurs through specific binding to the PKC C1 domains [1, 2] Despite their high homology and similar substrate specificity in vitro, PKC isozymes possess striking functional selectivity in cells due to their distinctive intracellular localization and differential access to substrates [1]. Did we establish unique patterns of gene expression controlled by individual PKCs, but we identified novel PKC␦-specific regulated genes implicated in LNCaP cell death. Our studies defined a differential utilization of PKC isozymes in gene expression regulation depending on the stimuli
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