Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
42
pubmed:dateCreated
2005-10-17
pubmed:abstractText
BAY 43-9006 is a kinase inhibitor that induces apoptosis in a variety of tumor cells. Here we report that treatment with BAY 43-9006 results in marked cytochrome c and AIF release into the cytosol, caspase-9, -8, -7, and -3 activation, and apoptosis in human leukemia cells (U937, Jurkat, and K562). Pronounced apoptosis was also observed in blasts from patients with acute myeloid leukemia. These events were accompanied by ERK1/2 inactivation and caspase-independent down-regulation of Mcl-1. Inducible expression of a constitutively active MEK1 construct did not prevent Mcl-1 down-regulation, suggesting that this event is not related to MEK/ERK pathway inactivation. Furthermore, BAY 43-9006 did not induce major changes in Mcl-1 mRNA levels monitored by real-time PCR or Mcl-1 promoter activity demonstrated by luciferase reporter assays, but it did enhance Mcl-1 down-regulation in actinomycin D-treated cells. Inhibition of protein synthesis by cycloheximide or proteasome function with MG132 and pulse-chase studies with [35S]methionine demonstrated that BAY 43-9006 did not diminish Mcl-1 protein stability, nor did it enhance Mcl-1 ubiquitination, but instead markedly attenuated Mcl-1 translation in association with the rapid and potent dephosphorylation of the eIF4E translation initiation factor. Finally, ectopic expression of Mcl-1 in leukemic cells markedly inhibited BAY 43-9006-mediated cytochrome c cytosolic release, caspase-9, -7, and -3 activation, as well as cell death, indicating that Mcl-1 operates upstream of cytochrome c release and caspase activation. Together, these findings demonstrate that BAY 43-9006 mediates cell death in human leukemia cells, at least in part, through down-regulation of Mcl-1 via inhibition of translation.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, http://linkedlifedata.com/resource/pubmed/chemical/Benzenesulfonates, http://linkedlifedata.com/resource/pubmed/chemical/CASP3 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/CASP7 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/CASP9 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Caspase 3, http://linkedlifedata.com/resource/pubmed/chemical/Caspase 7, http://linkedlifedata.com/resource/pubmed/chemical/Caspase 9, http://linkedlifedata.com/resource/pubmed/chemical/Caspases, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Neoplasm Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-bcl-2, http://linkedlifedata.com/resource/pubmed/chemical/Pyridines, http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger, http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin, http://linkedlifedata.com/resource/pubmed/chemical/myeloid cell leukemia sequence 1..., http://linkedlifedata.com/resource/pubmed/chemical/sorafenib
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
21
pubmed:volume
280
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
35217-27
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:16109713-Antineoplastic Agents, pubmed-meshheading:16109713-Apoptosis, pubmed-meshheading:16109713-Benzenesulfonates, pubmed-meshheading:16109713-Caspase 3, pubmed-meshheading:16109713-Caspase 7, pubmed-meshheading:16109713-Caspase 9, pubmed-meshheading:16109713-Caspases, pubmed-meshheading:16109713-Cell Line, Tumor, pubmed-meshheading:16109713-Chromatography, pubmed-meshheading:16109713-Dose-Response Relationship, Drug, pubmed-meshheading:16109713-Down-Regulation, pubmed-meshheading:16109713-Enzyme Inhibitors, pubmed-meshheading:16109713-Genes, Reporter, pubmed-meshheading:16109713-Humans, pubmed-meshheading:16109713-Immunoblotting, pubmed-meshheading:16109713-Immunoprecipitation, pubmed-meshheading:16109713-Jurkat Cells, pubmed-meshheading:16109713-K562 Cells, pubmed-meshheading:16109713-Leukemia, pubmed-meshheading:16109713-Neoplasm Proteins, pubmed-meshheading:16109713-Phosphorylation, pubmed-meshheading:16109713-Promoter Regions, Genetic, pubmed-meshheading:16109713-Protein Biosynthesis, pubmed-meshheading:16109713-Proto-Oncogene Proteins c-bcl-2, pubmed-meshheading:16109713-Pyridines, pubmed-meshheading:16109713-RNA, Messenger, pubmed-meshheading:16109713-Reverse Transcriptase Polymerase Chain Reaction, pubmed-meshheading:16109713-Subcellular Fractions, pubmed-meshheading:16109713-Time Factors, pubmed-meshheading:16109713-Transcription, Genetic, pubmed-meshheading:16109713-Transfection, pubmed-meshheading:16109713-U937 Cells, pubmed-meshheading:16109713-Ubiquitin
pubmed:year
2005
pubmed:articleTitle
Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation.
pubmed:affiliation
Departments of Medicine, Biochemistry, and Pharmacology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural