title: MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme.
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.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sung-Suk
authors.initials: SS
authors.lastname: Suh
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoo
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nuovo
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Jeon
authors.forename: Seokho
authors.initials: S
authors.lastname: Kim
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Lee
authors.forename: Taewan
authors.initials: T
authors.lastname: Kim
authors.forename: Arianna
authors.initials: A
authors.lastname: Bakàcs
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
authors.forename: Flavia
authors.initials: F
authors.lastname: Pichiorri
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D050687:E2F1 Transcription Factor / Q000502:physiology; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D014158:Transcription, Genetic; D000077004:Tuberous Sclerosis Complex 1 Protein; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2