Regulation of Transcriptional Networks by PKC Isozymes: Identification of c-Rel as a Key Transcription Factor for PKC-Regulated Genes

• Published in: PloS one Vol. 8; no. 6; p. e67319
• Main Authors: Garg, Rachana, Caino, M Cecilia, Kazanietz, Marcelo G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.06.2013; Public Library of Science (PLoS)
• Subjects: Angiogenesis; Apoptosis; Bioinformatics; Biological activity; Biology; Cancer; Cell cycle; Cyclic AMP response element-binding protein; Diglycerides; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Gene Regulatory Networks; Genes; Genomes; Humans; Inflammation; Inflammatory response; Isoenzymes; Kinases; Laboratories; Male; Medical research; Medicine; Networks; NF-κB protein; Oct-1 protein; Pharmacology; Promoter Regions, Genetic; Promoters; Prostate cancer; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Protein kinase C; Protein Kinase C - genetics; Proteins; Proto-Oncogene Proteins c-rel - genetics; Proto-Oncogene Proteins c-rel - metabolism; Regulatory Elements, Transcriptional; RNA-mediated interference; Serine; Threonine; Transcription activation; Transcription factors; Transcriptional Activation; Tumor Cells, Cultured
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0067319

Activation of protein kinase C (PKC), a family of serine-threonine kinases widely implicated in cancer progression, has major impact on gene expression. In a recent genome-wide analysis of prostate cancer cells we identified distinctive gene expression profiles controlled by individual PKC isozymes and highlighted a prominent role for PKCδ in transcriptional activation. Here we carried out a thorough bioinformatics analysis to dissect transcriptional networks controlled by PKCα, PKCδ, and PKCε, the main diacylglycerol/phorbol ester PKCs expressed in prostate cancer cells. Despite the remarkable differences in the patterns of transcriptional responsive elements (REs) regulated by each PKC, we found that c-Rel represents the most frequent RE in promoters regulated by all three PKCs. In addition, promoters of PKCδ-regulated genes were particularly enriched with REs for CREB, NF-E2, RREB, SRF, Oct-1, Evi-1, and NF-κB. Most notably, by using transcription factor-specific RNAi we were able to identify subsets of PKCδ-regulated genes modulated by c-Rel and CREB. Furthermore, PKCδ-regulated genes condensed under the c-Rel transcriptional regulation display significant functional interconnections with biological processes such as angiogenesis, inflammatory response, and cell motility. Our study identified candidate transcription factors in the promoters of PKC regulated genes, in particular c-Rel was found as a key transcription factor in the control of PKCδ-regulated genes. The deconvolution of PKC-regulated transcriptional networks and their nodes may greatly help in the identification of PKC effectors and have significant therapeutics implications.