Linked Life Data

12821941

Source:http://linkedlifedata.com/resource/pubmed/id/12821941

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
26
pubmed:dateCreated
2003-6-24
pubmed:abstractText
ARG is a tyrosine kinase closely related to ABL, which is oncogenic when fused to the transcriptional repressor ETV6 (ETS translocation variant 6). In this study, we investigated the growth-inhibitory effect of STI571 (signal transduction inhibitor number 571) on ETV6/ARG-expressing cells and its molecular mechanisms using HT93A, a cell line derived from a patient with AML-M3 carrying t(1;12). STI571 effectively suppressed overall tyrosyl phosphorylation of intracellular proteins including ETV6/ARG fusion protein, as well as the growth of HT93A cells with an IC(50) of 200 nM. The growth inhibition was primarily because of cell cycle arrest at G1 phase when cells were treated with 100 nM STI571 for 48 h, and apoptosis was induced after longer exposure (72 h) or by a higher dose (1000 nM). STI571 increased the amount of p18/INK4c after 2 h of culture, when the cell cycle pattern was not yet affected, but not that of other CDK inhibitors (CKI). p18/INK4c was more abundant in G1-enriched fractions than in S- and G2/M-enriched fractions of STI571-treated HT93A cells, suggesting that the upregulation of p18/INK4c expression correlates with the cell cycle arrest. Treatment of HT93A cells with antisense oligonucleotides against the Ink4c gene abrogated the growth inhibition by STI571. These results suggest that leukemogenesis by an aberrant ARG kinase involves the suppression of p18/INK4c, which is ubiquitously expressed and considered the major CKI in hematopoietic stem cells. STI571 can be an effective drug for the treatment of leukemias with deregulated ARG kinase activity.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0950-9232
pubmed:author
pubmed:issnType
Print
pubmed:day
26
pubmed:volume
22
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4074-82
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:12821941-Antineoplastic Agents, pubmed-meshheading:12821941-Apoptosis, pubmed-meshheading:12821941-Blotting, Northern, pubmed-meshheading:12821941-Blotting, Western, pubmed-meshheading:12821941-Cell Cycle, pubmed-meshheading:12821941-Cell Cycle Proteins, pubmed-meshheading:12821941-Cell Survival, pubmed-meshheading:12821941-Cyclin-Dependent Kinase Inhibitor p18, pubmed-meshheading:12821941-Dose-Response Relationship, Drug, pubmed-meshheading:12821941-Enzyme Inhibitors, pubmed-meshheading:12821941-Flow Cytometry, pubmed-meshheading:12821941-G1 Phase, pubmed-meshheading:12821941-Gene Expression Regulation, pubmed-meshheading:12821941-Humans, pubmed-meshheading:12821941-Inhibitory Concentration 50, pubmed-meshheading:12821941-Oligonucleotides, Antisense, pubmed-meshheading:12821941-Phosphorylation, pubmed-meshheading:12821941-Piperazines, pubmed-meshheading:12821941-Precipitin Tests, pubmed-meshheading:12821941-Pyrimidines, pubmed-meshheading:12821941-RNA, Messenger, pubmed-meshheading:12821941-Time Factors, pubmed-meshheading:12821941-Tumor Cells, Cultured, pubmed-meshheading:12821941-Tumor Suppressor Proteins, pubmed-meshheading:12821941-Up-Regulation
pubmed:year
2003
pubmed:articleTitle
Suppression of ARG kinase activity by STI571 induces cell cycle arrest through up-regulation of CDK inhibitor p18/INK4c.
pubmed:affiliation
Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, Tochigi 329-0498, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't