jf5b01005_si_001.pdf (92.66 kB)
Up-Regulation of miR-34a Expression in Response to the Luteolin-Induced Neurite Outgrowth of PC12 Cells
journal contribution
posted on 2015-04-29, 00:00 authored by Pei-Yi Chen, Ming-Jiuan Wu, Heng-Yuan Chang, Mi-Hsueh Tai, Chi-Tang Ho, Jui-Hung YenLuteolin (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.