miR-34a repression of SIRT1 regulates apoptosis
miR-34a repression of SIRT1 regulates apoptosis
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DOI：
10.1073/pnas.0801613105
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发表时间：
2008-09-09
影响因子：
11.1
通讯作者：
Lowenstein, Charles J.
中科院分区：
文献类型：
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作者：
Yamakuchi, Munekazu;Ferlito, Marcella;Lowenstein, Charles J.
microRNA 34 a（miR-34 a）是一种肿瘤抑制基因，但它如何调节细胞增殖还不完全清楚。我们现在表明microRNA miR-34 a调节沉默信息调节因子1（SIRT 1）的表达。miR-34 a通过SIRT 1的3' UTR内的miR-34 a结合位点抑制SIRT 1表达。miR-34对SIRT 1的抑制导致乙酰化p53和p21及p53转录靶点的表达增加，p21和p53转录靶点分别调节细胞周期和细胞凋亡。此外，miR-34对SIRT 1的抑制最终导致WT人结肠癌细胞的凋亡，但不导致缺乏p53的人结肠癌细胞的凋亡。最后，miR-34 a本身是p53的转录靶点，表明p53和miR-34 a之间存在正反馈环。因此，miR-34 a部分地通过SIRT 1-p53途径作为肿瘤抑制因子发挥作用。
MicroRNA 34a (miR-34a) is a tumor suppressor gene, but how it regulates cell proliferation is not completely understood. We now show that the microRNA miR-34a regulates silent information regulator 1 (SIRT1) expression. MiR-34a inhibits SIRT1 expression through a miR-34a-binding site within the 3' UTR of SIRT1. MiR-34 inhibition of SIRT1 leads to an increase in acetylated p53 and expression of p21 and PUMA, transcriptional targets of p53 that regulate the cell cycle and apoptosis, respectively. Furthermore, miR-34 suppression of SIRT1 ultimately leads to apoptosis in WT human colon cancer cells but not in human colon cancer cells lacking p53. Finally, miR-34a itself is a transcriptional target of p53, suggesting a positive feedback loop between p53 and miR-34a. Thus, miR-34a functions as a tumor suppressor, in part, through a SIRT1-p53 pathway.