Document Detail


Status of p53 in human cancer cells does not predict efficacy of CHK1 kinase inhibitors combined with chemotherapeutic agents.
MedLine Citation:
PMID:  20729914     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
DNA damage checkpoints cause cell cycle arrest, allowing DNA repair before resumption of the cell cycle. These checkpoints can be activated through several signaling pathways. Checkpoint activators include p53, checkpoint kinase 1 (CHK1), checkpoint kinase 2 and/or MAPKAP kinase 2 (MK2). Many cancer cells lack p53 activity and, therefore, depend on alternative checkpoint activators to arrest the cell cycle following DNA damage. Inhibition of these pathways is expected to specifically sensitize these p53-deficient cells to DNA damage caused by chemotherapy. Using isogenic p53-proficient and p53-deficient cancer cell lines, we show that inactivation of CHK1, but not MK2, abrogates cell cycle arrest following chemotherapy, specifically in p53-deficient cells. However, we show that CHK1 is required to maintain genome integrity and cell viability, and that p53-proficient cells are no less sensitive than p53-deficient cells to CHK1 inhibition in the presence of DNA damage. Thus, combining CHK1 inhibition with DNA damage does not lead to preferential killing of p53-deficient over p53-proficient cells, and inhibiting CHK1 does not appear to be a promising approach for potentiation of cancer chemotherapy.
Authors:
S Zenvirt; N Kravchenko-Balasha; A Levitzki
Related Documents :
9150394 - Role of p21waf1/cip1/sdi1 in cell death and dna repair as studied using a tetracycline-...
10622254 - P53 inhibition by the lana protein of kshv protects against cell death.
17949684 - P53-dependent change in replication timing of the human genome.
18272544 - Activated neutrophils induce an hmsh2-dependent g2/m checkpoint arrest and replication ...
6094244 - T cell growth factors from adult t cell leukemia virus-transformed cell lines.
8890314 - Ionic mechanisms underlying synchronized oscillations and propagating waves in a model ...
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-08-23
Journal Detail:
Title:  Oncogene     Volume:  29     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-24     Completed Date:  2011-01-11     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  6149-59     Citation Subset:  IM    
Affiliation:
Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Cell Cycle / drug effects
Cell Line, Tumor
Cell Survival
DNA Damage
Genes, p53 / physiology*
Humans
Intracellular Signaling Peptides and Proteins / physiology
Neoplasms / drug therapy*,  genetics,  pathology
Protein Kinase Inhibitors / administration & dosage*
Protein Kinases / physiology*
Protein-Serine-Threonine Kinases / physiology
Chemical
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; 0/Protein Kinase Inhibitors; EC 2.7.-/Protein Kinases; EC 2.7.1.-/MAP-kinase-activated kinase 2; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Identification of Siah-interacting protein as a potential regulator of apoptosis and curcumin resist...
Next Document:  Mast cells have a protumorigenic role in human thyroid cancer.