Linked Life Data

12429947

Source:http://linkedlifedata.com/resource/pubmed/id/12429947

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2002-11-13
pubmed:abstractText
Interactions between the protein kinase inhibitor UCN-01 and the PKC activator phorbol ester (PMA) have been examined in relation to differentiation and apoptosis in human myelomonocytic leukemia cells (U937). Coadministratation of 100 nM UCN-01 with a low concentration of PMA e.g., 2 nM, inhibited rather than promoted differentiation, reflected by reduced surface expression of the monocytic maturation marker CD11b and diminished cell adherence. Instead, administration of UCN-01 with PMA led to a marked increase in mitochondrial injury (e.g, cytochrome c release), activation of caspases-3 and -8, Bid cleavage, PARP degradation, and apoptosis, accompanied by a substantial reduction in viability and clonogenic survival. These phenomena were associated with multiple perturbations in cell cycle regulatory events, including abrogation of p21(CIP1) induction, p27(KIP1) cleavage, down-regulation of cyclin D1, dephosphorylation (activation) of p34cdc2, and degradation of underphosphorylated pRb. Potentiation of PMA-mediated apoptosis was partially mimicked by caffeine suggesting the involvement of Chk1 in the potentiation of apoptosis. Induction of cell death by UCN-01 and PMA was increased in cells stably expressing a p21(CIP1) mRNA antisense construct, suggesting that p21(CIP1) expression may protect cells from the lethal effects of this drug combination. Finally, ectopic expression of a Bcl-2 but not dominant-negative caspase-8 protected cells from UCN-01/PMA-mediated apoptosis, suggesting the lethal effects of this combination primarily involves the mitochondrial rather than the TNF-related extrinsic apoptotic pathway. Taken together, these findings suggest that UCN-01 disrupts a variety of cell cycle events in leukemic cells exposed to the maturation-inducing agent PMA, causing cells to engage an apoptotic rather than a differentiation-related program.
pubmed:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1538-4101
pubmed:author
pubmed:issnType
Print
pubmed:volume
1
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
273-81
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:12429947-Alkaloids, pubmed-meshheading:12429947-Antineoplastic Agents, pubmed-meshheading:12429947-Apoptosis, pubmed-meshheading:12429947-Blotting, Western, pubmed-meshheading:12429947-Carcinogens, pubmed-meshheading:12429947-Cell Differentiation, pubmed-meshheading:12429947-Cell Survival, pubmed-meshheading:12429947-Clinical Trials as Topic, pubmed-meshheading:12429947-Cytochrome c Group, pubmed-meshheading:12429947-Dose-Response Relationship, Drug, pubmed-meshheading:12429947-Enzyme Inhibitors, pubmed-meshheading:12429947-Genes, Dominant, pubmed-meshheading:12429947-Humans, pubmed-meshheading:12429947-Leukemia, pubmed-meshheading:12429947-Models, Biological, pubmed-meshheading:12429947-Staurosporine, pubmed-meshheading:12429947-Tetradecanoylphorbol Acetate, pubmed-meshheading:12429947-Time Factors, pubmed-meshheading:12429947-Tumor Cells, Cultured, pubmed-meshheading:12429947-U937 Cells
pubmed:articleTitle
UCN-01 (7-hydroxystauorsporine) blocks PMA-induced maturation and reciprocally promotes apoptosis in human myelomonocytic leukemia cells (U937).
pubmed:affiliation
Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't