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miR-34a induces the down-regulation of both E2F1 and B-Myb oncogenes in leukemic cells.
MedLine Citation:
PMID:  21367750     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
PURPOSE: To elucidate new molecular mechanisms able to down-regulated the mRNA levels of key oncogenes, such as B-Myb and E2F1, in a therapeutic perspective. EXPERIMENTAL DESIGN: B-Myb and E2F1 mRNA levels were evaluated in primary B chronic lymphocytic leukemia (B-CLL, n=10), acute myeloid leukemia (AML, n=5) patient cells, in a variety of p53wild-type and p53mutated/deleted leukemic cell lines, as well as in primary endothelial cells and fibroblasts. Knock-down experiments with siRNA for p53 and E2F1 and overexpression experiments with miR34a were performed to elucidate the role of these pathways in promoting B-Myb down-regulation.RESULTS: In vitro exposure to Nutlin-3, a non-genotoxic activator of p53, variably down-regulated the expression of B-Myb in primary leukemic cells, in p53wild-type myeloid (OCI, MOLM) and lymphoblastoid (SKW6.4, EHEB) but not in p53mutated (NB4, BJAB, MAVER) or p53deleted (HL-60) leukemic cell lines. The transcriptional repression of B-Myb was observed also in primary normal endothelial cells and fibroblasts. B-Myb down-regulation played a critical role in the cell cycle block in G1 phase induced by Nutlin-3, as demonstrated by transfection experiments with specific siRNA. Moreover, we have provided experimental evidence suggesting that miR-34a is a central mediator in the repression of B-Myb both directly and through E2F1. CONCLUSIONS: Due to the role of B-Myb and E2F1 transcription factors in controlling cell cycle progression of leukemic cells, the down-regulation of these oncogenes by miR-34a suggests the usefulness of therapeutic approaches aimed to modulate the levels of miR-34a.
Authors:
Giorgio Zauli; Rebecca Voltan; Maria Grazia di Iasio; Raffaella Bosco; Elisabetta Melloni; Maria Elena Sana; Paola Secchiero
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-3-2
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  -     ISSN:  1078-0432     ISO Abbreviation:  -     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-3-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Morphology and Embryology, University of Ferrara.
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