Differential Regulation of Gene Expression by Protein Kinase C Isozymes as Determined by Genome-wide Expression Analysis

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 PKC alpha, PKC delta, and PKC epsilon, which are remarkably different in cells growing in serum or in response to phorbol ester stimulation. PKC delta is the most relevant isoform in controlling the induction of genes by phorbol ester stimulation, whereas PKC epsilon predominantly regulates gene expression in serum. We also established that two PKC delta-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.