Nitroalkene Fatty Acids Mediate Activation of Nrf2/ARE-Dependent and PPAR纬-Dependent Transcription by Distinct Signaling Pathways and with Significantly Different Potencies

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• 作者：Darcy J. P. Bates ; Pamela K. Smitherman ; Alan J. Townsend ; S. Bruce King ; Charles S. Morrow
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：September 13, 2011
• 年：2011
• 卷：50
• 期：36
• 页码：7765-7773
• 全文大小：413K
• 年卷期：v.50,no.36(September 13, 2011)
• ISSN：1520-4995

文摘

Naturally occurring nitroalkene fatty acids (NAs) derived from oleic (NO₂-OA) and linoleic (NO₂-LA) acids mediate a variety of cellular responses. We examined the signaling pathways involved in NA activation of Nrf2/ARE-dependent versus PPAR纬/PPRE-dependent transcription in human MCF7 breast cancer cells. Additionally, we compared the relative potencies of NO₂-OA and NO₂-LA in activating these two transcriptional programs. Here it is demonstrated that, in addition to the direct adduct formation of NA with the Nrf2 inhibitory protein, Keap1, shown by others, NA activation of Nrf2/ARE-mediated transcription results from increased nuclear Nrf2 levels and depends upon activation of the PI3K/AKT and PKC, but not ERK and JNK MAPK, signaling pathways. Examination of the relationship between NA stimulation of the Nrf2/ARE versus PPAR纬/PPRE transcriptional programs revealed concentration-dependent activation of distinct signaling pathways that were readily distinguished by selective attenuation of Nrf2/ARE-dependent, but not PPAR纬-dependent, transcription by inhibitors of PI3K and PKC. Moreover, measurable, statistically significant activation of PPAR纬/PPRE-dependent transcription occurred at nanomolar concentrations of NAs鈥攖he 12-NO₂ isomer of NO₂-LA showing the most potent activity鈥攚hereas significant activation of Nrf2/ARE-dependent transcription occurred at much higher NA concentrations (鈮? 渭M) with the NO₂-OA isomers the most potent. These findings have implications for the physiological roles of NAs, suggesting that, at concentrations likely to be encountered in vivo, their direct activation of PPAR纬 transcription will dominate over their electrophilic activation of Nrf2 antioxidant/protective responses.