Yamakuchi Munekazu, Ferlito Marcella, Lowenstein Charles J
Departments of Medicine and Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13421-6. doi: 10.1073/pnas.0801613105. Epub 2008 Aug 28.
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.
微小RNA 34a（miR - 34a）是一种肿瘤抑制基因，但其如何调节细胞增殖尚未完全明确。我们现在发现，微小RNA miR - 34a可调节沉默信息调节因子1（SIRT1）的表达。MiR - 34a通过SIRT1 3'非翻译区（UTR）内的miR - 34a结合位点抑制SIRT1的表达。MiR - 34对SIRT1的抑制导致乙酰化p53增加以及p21和PUMA的表达增加，p21和PUMA分别是p53的转录靶点，它们分别调节细胞周期和凋亡。此外，miR - 34对SIRT1的抑制最终导致野生型人结肠癌细胞凋亡，但在缺乏p53的人结肠癌细胞中则不会。最后，miR - 34a本身是p53的转录靶点，提示p53与miR - 34a之间存在正反馈回路。因此，miR - 34a部分通过SIRT1 - p53途径发挥肿瘤抑制作用。
