MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme.

Suh SS, Yoo JY, Nuovo GJ, Jeon YJ, Kim S, Lee TJ, Kim T, Bakàcs A, Alder H, Kaur B, Aqeilan RI, Pichiorri F, Croce CM
Proc Natl Acad Sci U S A. 2012 109 (14): 5316-21

PMID: 22431589 · PMCID: PMC3325690 · DOI:10.1073/pnas.1202465109

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.

MeSH Terms (13)

Brain Neoplasms Cell Cycle Cell Proliferation E2F1 Transcription Factor Glioblastoma Humans MicroRNAs Proto-Oncogene Proteins c-mdm2 Proto-Oncogene Proteins c-myc Transcription, Genetic Tuberous Sclerosis Complex 1 Protein Tumor Suppressor Protein p53 Tumor Suppressor Proteins

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