Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
J Biol Chem. 2011 Apr 1;286(13):11254-64. doi: 10.1074/jbc.M110.194332. Epub 2011 Jan 20.
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.
蛋白激酶 C（PKC）同工酶是参与正常生理和疾病的关键信号转导物，并且广泛涉及癌症的进展。尽管我们对 PKC 同工酶及其效应物调节的信号通路有广泛的了解，但关于 PKC 家族的各个成员如何调节基因转录的信息基本上是没有的。在这里，我们通过使用二酰基甘油/佛波酯调节的 PKC 的 RNAi 耗竭来报告首次使用微阵列进行的 PKC 同工酶特异性的全基因表达分析。对这些微阵列数据的深入分析揭示了 PKCα、PKCδ 和 PKCε 控制基因表达的独特模式，这些模式在血清中生长的细胞或对佛波酯刺激的反应中差异显著。PKCδ 是控制佛波酯刺激诱导基因表达的最相关同工酶，而 PKCε 主要在血清中调节基因表达。我们还确定了两个 PKCδ 调节的基因 FOSL1 和 BCL2A1，介导了前列腺癌细胞中佛波酯或化疗药物依托泊苷的凋亡作用。我们的研究为 PKC 同工酶的新型转录效应物的建立提供了独特的机会，并且可能具有重要的功能和治疗意义。
