Differential Regulation of Gene Expression by Protein Kinase C Isozymes as Determined by Genome-wide Expression Analysis
Differential Regulation of Gene Expression by Protein Kinase C Isozymes as Determined by Genome-wide Expression Analysis
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DOI：
10.1074/jbc.m110.194332
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发表时间：
2011-04-01
影响因子：
4.8
通讯作者：
Kazanietz, Marcelo G.
中科院分区：
文献类型：
--
作者：
Caino, M. Cecilia;von Burstin, Vivian A.;Kazanietz, Marcelo G.
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，并广泛参与癌症进展。尽管我们对PKC同工酶及其效应器调节的信号通路有广泛的了解，但基本上没有关于PKC家族个体成员如何调节基因转录的信息。在这里，我们报告了第一个PKC同工酶特异性的全球基因表达分析，通过微阵列使用RNAi耗尽二酰基甘油/磷酯调节的PKCs。对微阵列数据的深入分析揭示了由PKC α、PKC δ和PKC epsilon控制的独特基因表达模式，它们在血清中生长的细胞或对磷酯刺激的反应中有显著不同。PKC δ是控制磷酸酯刺激诱导基因的最相关的亚型，而PKC ε主要调节血清中的基因表达。我们还发现两个PKC δ调节基因FOSL1和BCL2A1介导前列腺癌细胞中佛波酯或化疗药物依托泊苷的凋亡作用。我们的研究为建立PKC同工酶的新型转录效应物提供了一个独特的机会，并且可能具有重要的功能和治疗意义。
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.