Document Detail

Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development.
MedLine Citation:
PMID:  20951946     Owner:  NLM     Status:  MEDLINE    
In multiple myeloma (MM), an incurable B cell neoplasm, mutation or deletion of p53 is rarely detected at diagnosis. Using small-molecule inhibitors of MDM2, we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. The results suggest that these miRNAs are positive regulators of p53 and that their downregulation plays a key role in MM development.
Flavia Pichiorri; Sung-Suk Suh; Alberto Rocci; Luciana De Luca; Cristian Taccioli; Ramasamy Santhanam; Wenchao Zhou; Don M Benson; Craig Hofmainster; Hansjuerg Alder; Michela Garofalo; Gianpiero Di Leva; Stefano Volinia; Huey-Jen Lin; Danilo Perrotti; Michael Kuehl; Rami I Aqeilan; Antonio Palumbo; Carlo M Croce
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer cell     Volume:  18     ISSN:  1878-3686     ISO Abbreviation:  Cancer Cell     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-18     Completed Date:  2010-11-03     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  101130617     Medline TA:  Cancer Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  367-81     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Department of Molecular Virology, Comprehensive Cancer Center, Ohio State University, Columbus, 43210, USA.
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MeSH Terms
Cell Cycle / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Chromosomes, Human, Pair 11 / genetics
DNA Methylation / drug effects,  genetics
Down-Regulation / drug effects,  genetics*
Gene Expression Regulation, Neoplastic / drug effects
Homeostasis / drug effects,  genetics*
Insulin-Like Growth Factor I / metabolism
MicroRNAs / genetics*
Models, Biological
Multiple Myeloma / genetics*,  pathology
Mutagens / toxicity
Neoplasm Invasiveness
Precancerous Conditions / genetics,  pathology*
Promoter Regions, Genetic / genetics
Proto-Oncogene Proteins c-mdm2 / genetics,  metabolism*
RNA, Messenger / genetics,  metabolism
Receptor, IGF Type 1 / metabolism
Tumor Suppressor Protein p53 / metabolism*
Grant Support
GTF03012//Telethon; K12 CA133250/CA/NCI NIH HHS
Reg. No./Substance:
0/MicroRNAs; 0/Mutagens; 0/RNA, Messenger; 0/Tumor Suppressor Protein p53; 67763-96-6/Insulin-Like Growth Factor I; EC, IGF Type 1; EC protein, human; EC Proteins c-mdm2
Comment In:
Cancer Cell. 2010 Oct 19;18(4):299-300   [PMID:  20951939 ]

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