MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme

被引:109
作者
Suh, Sung-Suk [1 ]
Yoo, Ji Young [2 ]
Nuovo, Gerard J. [1 ]
Jeon, Young-Jun [1 ]
Kim, Seokho [3 ]
Lee, Tae Jin [1 ]
Kim, Taewan [1 ]
Bakacs, Arianna [4 ]
Alder, Hansjuerg [1 ]
Kaur, Balveen [2 ]
Aqeilan, Rami I. [1 ,5 ]
Pichiorri, Flavia [6 ]
Croce, Carlo M. [1 ]
机构
[1] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Ctr Comprehens Canc, Columbus, OH 43210 USA
[2] Ohio State Univ, Dardinger Lab Neurooncol & Neurosci, Dept Neurol Surg, Comprehens Canc Ctr,Med Ctr, Columbus, OH 43220 USA
[3] Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK 73104 USA
[4] Azienda Complesso Osped San Filippo Neri, Unita Operat Complessa Anat Patol, I-00135 Rome, Italy
[5] Hebrew Univ Jerusalem, Hadassah Med Sch, Lautenberg Ctr Gen & Tumor Immunol, Dept Immunol & Canc Res,Inst Med Res Israel Canad, IL-91120 Jerusalem, Israel
[6] Ohio State Univ, Coll Med, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA
关键词
GROWTH-FACTOR RECEPTOR; CELL-CYCLE ARREST; C-MYC; PROMOTES APOPTOSIS; DOWN-REGULATION; P53; GENE; MDM2; INHIBITION; EXPRESSION; CANCER;
D O I
10.1073/pnas.1202465109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
MicroRNAs (miRNAs) are increasingly implicated in regulating cancer initiation and progression. In this study, twomiRNAs, 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 transfectedmiR-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.
引用
收藏
页码:5316 / 5321
页数:6
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