title: Up-Regulation of miR-34a Expression in Response to the Luteolin-Induced Neurite Outgrowth of PC12 Cells.
abstract: Luteolin (3',4',5,7-tetrahydroxyflavone), a flavonoid found in several vegetables and fruits, has been reported to possess neurotrophic activities that are associated with its capacity to promote neuronal survival and differentiation. In the present study, we report for the first time a genomewide screen for microRNAs (miRNAs) regulated during the luteolin-mediated neurite outgrowth of PC12 cells. We found that after luteolin treatment, the abundance of 16 miRNAs was markedly up-regulated and that of 3 miRNAs was down-regulated in PC12 cells. The induction of miR-34a by luteolin was the most pronounced among these differentially expressed miRNAs. The correlation between miR-34a down-regulation and decreased luteolin-mediated neurite outgrowth may indicate a mechanism by which miR-34a may act as a modulator of neuronal differentiation. Furthermore, we found that luteolin enhanced the phosphorylation of p53 at Ser15, which was associated with the promotion of miR-34a transcription and neurite outgrowth. Moreover, the level of sirtuin 1 (SIRT1), a known miR-34a target, was reduced during luteolin-induced neurite outgrowth. In turn, the level of acetylated p53, a substrate of SIRT1, was correspondingly increased in luteolin-treated PC12 cells. In addition to p53 activation, we further identified that luteolin-induced miR-34a transcription and neurite outgrowth involved the activation of the JNK and p38 MAPK pathways. However, the inhibition of JNK and p38 MAPK activation did not block luteolin-induced p53 activation in PC12 cells. Our findings suggested that the activation of both p53-dependent and p53-independent miR-34a/SIRT1 pathways plays a critical role in the mechanisms underlying luteolin-induced neuritogenesis.
authors: †Center of Medical Genetics, Buddhist Tzu Chi General Hospital, Hualien 970, Taiwan.
authors: Pei-Yi
authors: PY
authors: Chen
authors: ‡Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan 717, Taiwan.
authors: Ming-Jiuan
authors: MJ
authors: Wu
authors: Heng-Yuan
authors: HY
authors: Chang
authors: Mi-Hsueh
authors: MH
authors: Tai
authors: #Department of Food Science, Rutgers University, 65 Dudley Road, New Brunswick, New Jersey 08901-8520, United States.
authors: Chi-Tang
authors: CT
authors: Ho
authors: ∥Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan.
authors: Jui-Hung
authors: JH
authors: Yen
mesh_terms: D000818:Animals; D047311:Luteolin / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C560944:MIRN34 microRNA, rat; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D048670:MAP Kinase Kinase 4; D047311:Luteolin
keywords: SIRT1; luteolin; miR-34a; neurite outgrowth; p53