Document Detail

The effect of folate deficiency on the cytotoxic and mutagenic responses to ethyl methanesulfonate in human lymphoblastoid cell lines that differ in p53 status.
MedLine Citation:
PMID:  11166026     Owner:  NLM     Status:  MEDLINE    
Folic acid deficiency acts synergistically with alkylating agents to increase genetic damage at the HPRT locus in Chinese hamster ovary cells in vitro and in rat splenocytes in vivo. The present studies extend these observations to human cells and, in addition, investigate the role of p53 activity on mutation induction. The human lymphoblastoid cell lines TK6 and WTK1 are derived from the same parental cell line (WI-L2), but WTK1 expresses mutant p53. Treatment of folate-replete or deficient WTK1 and TK6 cells with increasing concentrations (0-50microg/ml) of ethyl methanesulfonate (EMS) resulted in significantly different HPRT mutation dose-response relationships (P<0.01), indicating that folate deficiency increased the EMS-induced mutant frequency in both cell lines, but with a greater effect in TK6 cells. Molecular analyses of 152 mutations showed that the predominant mutation (65%) in both cell types grown in the presence or absence of folic acid was a G>A transition on the non-transcribed strand. These transitions were mainly at non-CpG sites, particularly when these bases were flanked 3' by a purine or on both sides by G:C base pairs. A smaller number of G>A transitions occurred on the transcribed strand (C>T=14%), resulting in 79% total G:C>A:T transitions. There were more genomic deletions in folate-deficient (15%) as compared to replete cells (4%) of both cell types. Mutations that altered RNA splicing were common in both cell types and under both folate conditions, representing 33% of the total mutations. These studies indicate that cells expressing p53 activity exhibit a higher rate of mutation induction but are more sensitive to the toxic effects of alkylating agents than those lacking p53 activity. Folate deficiency tends to reduce toxicity but increase mutation induction after EMS treatment. The p53 gene product did not have a major influence on the molecular spectrum after treatment with EMS, while folate deficiency increased the frequency of deletions in both cell types.
R F Branda; J P O'Neill; E M Brooks; L M Trombley; J A Nicklas
Related Documents :
12920036 - Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leuk...
11319606 - Staurosporine-induced apoptosis of hpv positive and negative human cervical cancer cell...
15236626 - Isoliquiritigenin inhibits the proliferation and induces the apoptosis of human non-sma...
7543816 - Attenuated response of p53 and p21 in primary cultures of human prostatic epithelial ce...
9409206 - Role of activin-a and follistatin in foam cell formation of thp-1 macrophages.
24599086 - Real-time label-free detection of dividing cells by means of lensfree video-microscopy.
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Mutation research     Volume:  473     ISSN:  0027-5107     ISO Abbreviation:  Mutat. Res.     Publication Date:  2001 Jan 
Date Detail:
Created Date:  2001-02-22     Completed Date:  2001-03-22     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0400763     Medline TA:  Mutat Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  51-71     Citation Subset:  IM    
Department of Medicine and The Vermont Cancer Center, University of Vermont, Burlington, VT 05405, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Antineoplastic Agents, Alkylating / pharmacology
Base Sequence
Cell Division / drug effects
Cell Line
DNA Mutational Analysis
Dose-Response Relationship, Drug
Ethyl Methanesulfonate / pharmacology*
Folic Acid / pharmacology*
Molecular Sequence Data
Mutagenesis / drug effects*
Mutagens / pharmacology
Tumor Suppressor Protein p53 / genetics,  pharmacology*
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Mutagens; 0/Tumor Suppressor Protein p53; 59-30-3/Folic Acid; 62-50-0/Ethyl Methanesulfonate

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Lung-specific mutagenicity and mutational spectrum in B6C3F1 lacI transgenic mice following inhalati...
Next Document:  Frequency of CD59 mutations induced in human-hamster hybrid A(L) cells by low-dose X-irradiation.