DNA adducts of decarbamoyl mitomycin C efficiently kill cells without wild-type p53 resulting from proteasome-mediated degradation of checkpoint protein 1.
| dc.contributor.author | Boamah, Ernest K | |
| dc.contributor.author | Brekman, Angelika | |
| dc.contributor.author | Tomasz, Maria | |
| dc.contributor.author | Myeku, Natura | |
| dc.contributor.author | Figueiredo-Pereira, Maria | |
| dc.contributor.author | Hunter, Senyene | |
| dc.contributor.author | Meyer, Joel | |
| dc.contributor.author | Bhosle, Rahul C | |
| dc.contributor.author | Bargonetti, Jill | |
| dc.coverage.spatial | United States | |
| dc.date.accessioned | 2011-06-21T17:27:12Z | |
| dc.date.issued | 2010-07-19 | |
| 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.description.version | Version of Record | |
| dc.identifier | ||
| dc.identifier.eissn | 1520-5010 | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.language.iso | en_US | |
| dc.publisher | American Chemical Society (ACS) | |
| dc.relation.ispartof | Chem Res Toxicol | |
| dc.relation.isversionof | 10.1021/tx900420k | |
| dc.relation.journal | Chemical research in toxicology | |
| 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 | ||
| dc.type | Journal article | |
| duke.contributor.orcid | Meyer, Joel|0000-0003-1219-0983 | |
| duke.date.pubdate | 2010-7-0 | |
| duke.description.issue | 7 | |
| duke.description.volume | 23 | |
| pubs.author-url | ||
| pubs.begin-page | 1151 | |
| pubs.end-page | 1162 | |
| pubs.issue | 7 | |
| pubs.organisational-group | Civil and Environmental Engineering | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | Duke Cancer Institute | |
| pubs.organisational-group | Environmental Sciences and Policy | |
| pubs.organisational-group | Global Health Institute | |
| pubs.organisational-group | Institutes and Centers | |
| pubs.organisational-group | Institutes and Provost's Academic Units | |
| pubs.organisational-group | Nicholas School of the Environment | |
| pubs.organisational-group | Pratt School of Engineering | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | University Institutes and Centers | |
| pubs.publication-status | Published | |
| pubs.volume | 23 |