p53-Responsive micrornas 192 and 215 are capable of inducing cell cycle arrest.
p53-Responsive micrornas 192 and 215 are capable of inducing cell cycle arrest.
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DOI：
10.1158/0008-5472.can-08-1569
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发表时间：
2008-12-15
期刊：
影响因子：
11.2
通讯作者：
Dobbelstein M
中科院分区：
文献类型：
--
作者：
Braun CJ;Zhang X;Savelyeva I;Wolff S;Moll UM;Schepeler T;Ørntoft TF;Andersen CL;Dobbelstein M
microRNA通过干扰特定靶mRNA的稳定性和/或翻译为基因表达提供了一个新的调控层。microRNA的总体水平在癌细胞中经常下调，并且减少一般microRNA加工增加转基因模型中的癌症发生，这表明至少一些microRNA可能在肿瘤抑制中起作用。因此，肿瘤抑制因子p53上调miR-34 a，这是一种有助于细胞凋亡和急性衰老的微小RNA。在这里，我们使用阵列杂交发现p53诱导两个额外的，相互关联的microRNA簇，导致miR-192，miR-194和miR-215的上调。在正常结肠组织中检测到高水平的相同microRNA，但在许多结肠癌样本中严重减少。另一方面，miR-192和它的表亲miR-215可以各自有助于增强CDKN 1A/p21水平、集落抑制、细胞周期停滞和细胞从固体支持物脱离。这些效应部分依赖于野生型p53的存在。拮抗内源性miR-192减弱5-氟尿嘧啶诱导的p21积聚。因此，miR-192和miR-215可以作为p53的效应子和调节子;它们似乎通过p21积累和细胞周期停滞来抑制癌发生。
microRNAs provide a novel layer of regulation for gene expression by interfering with the stability and/or translation of specific target mRNAs. Overall levels of microRNAs are frequently down-regulated in cancer cells, and reducing general microRNA processing increases cancerogenesis in transgenic models, suggesting that at least some microRNAs might act as effectors in tumor suppression. Accordingly, the tumor suppressor p53 up-regulates miR-34a, a microRNA that contributes to apoptosis and acute senescence. Here, we used array hybridization to find that p53 induces two additional, mutually related clusters of microRNAs, leading to the up-regulation of miR-192, miR-194, and miR-215. The same microRNAs were detected at high levels in normal colon tissue but were severely reduced in many colon cancer samples. On the other hand, miR-192 and its cousin miR-215 can each contribute to enhanced CDKN1A/p21 levels, colony suppression, cell cycle arrest, and cell detachment from a solid support. These effects were partially dependent on the presence of wild-type p53. Antagonizing endogenous miR-192 attenuated 5-fluorouracil–induced accumulation of p21. Hence, miR-192 and miR-215can act as effectors as well as regulators of p53; they seem to suppress cancerogenesis through p21 accumulation and cell cycle arrest.