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miR‐605 joins p53 network to form a p53: miR‐605 :Mdm2 positive feedback loop in response to stress
Author(s) -
Xiao Jiening,
Lin Huixian,
Luo Xiaobin,
Luo Xiaoyan,
Wang Zhiguo
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.347
Subject(s) - biology , joins , loop (graph theory) , positive feedback , feedback loop , mdm2 , negative feedback , genetics , physics , combinatorics , computer science , gene , electrical engineering , mathematics , computer security , voltage , quantum mechanics , programming language , engineering
In cancers with wild‐type (WT) p53 status, the function of p53 is inhibited through direct interaction with Mdm2 oncoprotein, a negative feedback loop to limit the function of p53. In response to cellular stress, p53 escapes the p53:Mdm2 negative feedback to accumulate rapidly to induce cell cycle arrest and apoptosis. We demonstrate herein that an microRNA miR‐605 is a new component in the p53 gene network, being transcriptionally activated by p53 and post‐transcriptionally repressing Mdm2. Activation of p53 upregulated miR‐605 via interacting with the promoter region of the gene. Overexpression of miR‐605 directly decreased Mdm2 expression at the post‐transcriptional level but indirectly increased the transcriptional activity of p53 on miR‐34a via downregulating Mdm2; knockdown of miR‐605 did the opposite. Mdm2 inhibitor upregulated expression of both miR‐34a and miR‐605 , which was mitigated by p53 inhibitor. miR‐605 preferentially induced apoptosis in WT p53‐expressing cells, an effect abolished by p53 inhibition. These results indicate that miR‐605 acts to interrupt p53:Mdm2 interaction to create a positive feedback loop aiding rapid accumulation of p53 to facilitate its function in response to stress.