Linked Life Data

15539958

Source:http://linkedlifedata.com/resource/pubmed/id/15539958

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2005-3-1
pubmed:abstractText
Chk1 (checkpoint kinase 1) is an evolutionarily conserved serine/threonine kinase involved in DNA damage responses. Originally identified as a kinase regulating the G2/M transition checkpoint, its role has broadened to include the S-phase checkpoint response and essential functions in early embryonic development. In this manuscript we investigated the potential of chemo-sensitization via ablation of Chk1 in cells treated with anti-metabolite cancer drugs, hydroxyurea (HU) and cytosine arabinoside (ara-C). Exposure to these replication interfering drugs in cells carrying Chk1 targeted siRNA provoked markedly increased rates of apoptosis. Although cell death was accompanied by an increase in p53 and activation of Chk2, the increased susceptibility to apoptosis was not dependent on p53 or Chk2. Additionally, we found that cells with reduced Chk1 expression displayed increased gamma-H2A.X expression, a marker for damaged DNA, and phosphorylated 32kDa subunit of replication protein A (RPA). Thus, Chk1 may play an essential role in maintaining DNA integrity during the replication block. Significantly, normal cells such as WS1 did not exhibit increased DNA damage or subsequent increases in apoptosis following replication stress, in the absence of Chk1. Thus, the essential role Chk1 plays in maintaining viability during the replication block in cancer cell lines can be exploited to sensitize cancer cells when abrogation of Chk1 is combined with DNA anti-metabolite chemotherapeutic drugs. Taken together, these data suggest that inhibition of Chk1 in combination with DNA anti-metabolite chemotherapy is a viable therapeutic strategy.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, http://linkedlifedata.com/resource/pubmed/chemical/Checkpoint kinase 1, http://linkedlifedata.com/resource/pubmed/chemical/Cytarabine, http://linkedlifedata.com/resource/pubmed/chemical/DNA, Neoplasm, http://linkedlifedata.com/resource/pubmed/chemical/H2AFX protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Histones, http://linkedlifedata.com/resource/pubmed/chemical/Hydroxyurea, http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases, http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering, http://linkedlifedata.com/resource/pubmed/chemical/Replication Protein A, http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Protein p53, http://linkedlifedata.com/resource/pubmed/chemical/checkpoint kinase 2
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1551-4005
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
4
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
131-9
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Chk1 is essential for tumor cell viability following activation of the replication checkpoint.
pubmed:affiliation
Department of Discovery Research, DNAX Research Incorporated, Palo Alto, California, USA.
pubmed:publicationType
Journal Article