Document Detail

4-hydroxynonenal and regulation of cell cycle: effects on the pRb/E2F pathway.
MedLine Citation:
PMID:  15288118     Owner:  NLM     Status:  MEDLINE    
The hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxidation, might negatively affect cell proliferation, arose from the observation that lipid peroxidation is very low in tumors. In leukemic cells HNE inhibited cell growth and reduced c-myc and c-myb expression. HNE also induced differentiation in different leukemic cell lines. In HL-60 human leukemic cells, HNE induced the accumulation of cells in the G(0)/G(1) phase of the cell cycle accompanied by a decrease of cyclins D1, D2, and A. Moreover, HNE caused an increase in p21 expression. As cyclin D/CDK2 and cyclin A/CDK2 phosphorylate pRB, these findings suggested that pRb phosphorylation could be affected by HNE. Hypophosphorylated pRb binds and inactivates the E2F transcription factors. HNE induced the dephosphorylation of pRb and the increase in pRb/E2F1 complexes, whereas pRb/E2F4 complexes were reduced, because HNE downregulated E2F4 protein expression. The analysis of E2F binding to the P2 c-myc promoter revealed that HNE caused a decrease in "free" E2F, as well as an increase in pRb (and pRB family members) bound to E2F, with consequent repression of the transcription. In conclusion, HNE reduces E2F transcriptional activity by modifying a number of genes involved in regulation of the pRb/E2F pathway.
Giuseppina Barrera; Stefania Pizzimenti; Mario U Dianzani
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Free radical biology & medicine     Volume:  37     ISSN:  0891-5849     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2004 Sep 
Date Detail:
Created Date:  2004-08-03     Completed Date:  2005-02-08     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  597-606     Citation Subset:  IM    
Department of Experimental Medicine and Oncology, Section of General Pathology, University of Turin, 10125 Torino, Italy.
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MeSH Terms
Aldehydes / pharmacology*
Cell Cycle / drug effects*
Cyclins / drug effects,  physiology
Growth Inhibitors / pharmacology*
HL-60 Cells
K562 Cells
Retinoblastoma Protein / drug effects,  metabolism
Transcription, Genetic / drug effects
Reg. No./Substance:
0/Aldehydes; 0/Cyclins; 0/Growth Inhibitors; 0/Retinoblastoma Protein; 29343-52-0/4-hydroxy-2-nonenal

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