MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme

Sung Suk Suh, Ji Young Yoo, Gerard J. Nuovo, Young Jun Jeon, Seokho Kim, Tae Jin Lee, Taewan Kim, Arianna Bakac̀s, Hansjuerg Alder, Balveen Kaur, Rami I. Aqeilan, Flavia Pichiorri*, Carlo M. Croce

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

Abstract

MicroRNAs (miRNAs) are increasingly implicated in regulating cancer initiation and progression. In this study, two miRNAs, miR-25 and -32, are identified as p53-repressed miRNAs by p53-dependent negative regulation of their transcriptional regulators, E2F1 and MYC. However, miR-25 and -32 result in p53 accumulation by directly targeting Mdm2 and TSC1, which are negative regulators of p53 and the mTOR (mammalian target of rapamycin) pathway, respectively, leading to inhibition of cellular proliferation through cell cycle arrest. Thus, there is a recurrent autoregulatory circuit involving expression of p53, E2F1, and MYC to regulate the expression of miR-25 and -32, which are miRNAs that, in turn, control p53 accumulation. Significantly, overexpression of transfected miR-25 and -32 in glioblastoma multiforme cells inhibited growth of the glioblastoma multiforme cells in mouse brain in vivo. The results define miR-25 and -32 as positive regulators of p53, underscoring their role in tumorigenesis in glioblastoma.

Original languageAmerican English
Pages (from-to)5316-5321
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number14
DOIs
StatePublished - 3 Apr 2012

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