Document Detail

The human immunodeficiency virus-1 Tat protein increases cell proliferation, alters sensitivity to zinc chelator-induced apoptosis, and changes Sp1 DNA binding in HeLa cells.
MedLine Citation:
PMID:  9882443     Owner:  NLM     Status:  MEDLINE    
The HIV-1 transcriptional regulatory protein Tat is a pleiotropic factor that represses expression of the human Mn-superoxide dismutase. Tat increases oxidative stress, as shown by decreased glutathione and NADPH levels. These redox changes enhance proliferation and apoptosis and alter the activity of zinc thiolate-containing proteins such as Sp1. Cells stably producing the Tat protein have an increased proliferation rate, which can be inhibited by pretreatment with the antioxidant mercaptopropionylglycine. Conversely, cells exposed to low concentrations of the oxidant paraquat are stimulated to divide. Intermediate and higher paraquat levels result in increased apoptosis or necrosis, respectively, suggesting that the physiological end point depends on the dose of oxidant used. Furthermore, treatment with the zinc chelator (N,N,N', N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) sensitizes HeLa-tat cells to apoptosis. In these cells, binding of the zinc-containing factor Sp1 to its DNA sequence is higher than in parental cells. Normal DNA binding is partially restored by pretreatment with a compound that mimics superoxide dismutase activity. Interestingly, Sp1-DNA interactions decrease more rapidly in the HeLa-tat cells after TPEN treatment. HeLa cell extracts incubated in the presence of purified Tat protein have increased Sp1 binding, consistent with the results observed in Tat-transfected cells. These results suggest that the Tat protein, via direct or indirect mechanisms, increases proliferation, sensitizes cells to apoptosis, and changes the conformation of Sp1, affecting its ability to bind to its cognate DNA sequence and to retain its zinc.
M Seve; A Favier; M Osman; D Hernandez; G Vaitaitis; N C Flores; J M McCord; S C Flores
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Archives of biochemistry and biophysics     Volume:  361     ISSN:  0003-9861     ISO Abbreviation:  Arch. Biochem. Biophys.     Publication Date:  1999 Jan 
Date Detail:
Created Date:  1999-02-11     Completed Date:  1999-02-11     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0372430     Medline TA:  Arch Biochem Biophys     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  165-72     Citation Subset:  IM; X    
Copyright Information:
Copyright 1999 Academic Press.
Laboratoire de Biologie du Stress Oxydant (LBSO), University of Grenoble, La Tronche, 38700, France.
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MeSH Terms
Apoptosis* / drug effects
Cell Division / drug effects
Cells, Cultured
Chelating Agents / pharmacology*
Gene Products, tat / genetics,  physiology*
HIV-1 / genetics*
Hela Cells
Sp1 Transcription Factor / metabolism*
Sulfhydryl Compounds / metabolism
Superoxide Dismutase / pharmacology
Zinc / metabolism*
tat Gene Products, Human Immunodeficiency Virus
Grant Support
Reg. No./Substance:
0/Chelating Agents; 0/Gene Products, tat; 0/Sp1 Transcription Factor; 0/Sulfhydryl Compounds; 0/tat Gene Products, Human Immunodeficiency Virus; 7440-66-6/Zinc; EC Dismutase

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