Show simple item record Boamah, EK Brekman, A Tomasz, M Myeku, N Figueiredo-Pereira, M Hunter, S Meyer, J Bhosle, RC Bargonetti, J
dc.coverage.spatial United States 2011-06-21T17:27:12Z 2010-07-19
dc.identifier.citation Chem Res Toxicol, 2010, 23 (7), pp. 1151 - 1162
dc.description.abstract The mitomycin derivative 10-decarbamoyl mitomycin C (DMC) more rapidly activates a p53-independent cell death pathway than mitomycin C (MC). We recently documented that an increased proportion of mitosene1-beta-adduct formation occurs in human cells treated with DMC in comparison to those treated with MC. Here, we compare the cellular and molecular response of human cancer cells treated with MC and DMC. We find the increase in mitosene 1-beta-adduct formation correlates with a condensed nuclear morphology and increased cytotoxicity in human cancer cells with or without p53. DMC caused more DNA damage than MC in the nuclear and mitochondrial genomes. Checkpoint 1 protein (Chk1) was depleted following DMC, and the depletion of Chk1 by DMC was achieved through the ubiquitin proteasome pathway since chemical inhibition of the proteasome protected against Chk1 depletion. Gene silencing of Chk1 by siRNA increased the cytotoxicity of MC. DMC treatment caused a decrease in the level of total ubiquitinated proteins without increasing proteasome activity, suggesting that DMC mediated DNA adducts facilitate signal transduction to a pathway targeting cellular proteins for proteolysis. Thus, the mitosene-1-beta stereoisomeric DNA adducts produced by the DMC signal for a p53-independent mode of cell death correlated with reduced nuclear size, persistent DNA damage, increased ubiquitin proteolysis and reduced Chk1 protein.
dc.format.extent 1151 - 1162
dc.language eng
dc.language.iso en_US en_US
dc.relation.ispartof Chem Res Toxicol
dc.relation.isversionof 10.1021/tx900420k
dc.subject Apoptosis
dc.subject Cell Line, Tumor
dc.subject Checkpoint Kinase 1
dc.subject DNA Adducts
dc.subject DNA Damage
dc.subject Gene Silencing
dc.subject Humans
dc.subject Mitomycin
dc.subject Mitomycins
dc.subject Proteasome Endopeptidase Complex
dc.subject Protein Kinases
dc.subject RNA Interference
dc.subject RNA, Small Interfering
dc.subject Tumor Suppressor Protein p53
dc.title DNA adducts of decarbamoyl mitomycin C efficiently kill cells without wild-type p53 resulting from proteasome-mediated degradation of checkpoint protein 1.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US 2010-7-0 en_US
duke.description.endpage 1162 en_US
duke.description.issue 7 en_US
duke.description.startpage 1151 en_US
duke.description.volume 23 en_US
dc.relation.journal Chemical research in toxicology en_US
pubs.issue 7
pubs.organisational-group /Duke
pubs.organisational-group /Duke/Institutes and Provost's Academic Units
pubs.organisational-group /Duke/Institutes and Provost's Academic Units/University Institutes and Centers
pubs.organisational-group /Duke/Institutes and Provost's Academic Units/University Institutes and Centers/Global Health Institute
pubs.organisational-group /Duke/Nicholas School of the Environment
pubs.organisational-group /Duke/Nicholas School of the Environment/Environmental Sciences and Policy
pubs.organisational-group /Duke/Pratt School of Engineering
pubs.organisational-group /Duke/Pratt School of Engineering/Civil and Environmental Engineering
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published
pubs.volume 23
dc.identifier.eissn 1520-5010

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