Document Detail

Phosphorylation of chk1 at serine-345 affected by topoisomerase I poison SN-38.
MedLine Citation:
PMID:  12370755     Owner:  NLM     Status:  MEDLINE    
Human head and neck squamous carcinoma cell lines, A253 and FaDu, were utilized to identify mediators associated with response to topoisomerase I poison, SN-38, a metabolite of irinotecan. The drug sensitivity of FaDu cells to SN-38 was significantly higher than that of the A253 cells. In A253 cells, G2/M arrest following drug treatment (0.35 microM SN-38, 2-h exposure) was accompanied by DNA fragmentation in the 50-300 kb range, but FaDu cells accumulated in S-phase concurrently with induction of smaller DNA fragmentation in the 4-80 kb range. Because the critical regulatory step in activating cdc2 during progression into mitosis appears to be dephosphorylation of Tyrosine 15 (Tyr15), we examined the Tyr15 phosphorylation status of cdc2 in both cell lines. Slightly increased levels of cdc2 phosphorylation was observed in the A253 cells, while reduced levels of cdc2 phosphorylation was noted in the FaDu cells, corresponding to the abrogation of the G2-phase arrest. Increased chk1 phosphorylation at Ser345 induced by SN-38 was accompanied by the observed G2 phase arrest in the A253 cell line, while significant downregulation of chk1 and cdc25C phosphorylation, which resulted in the abrogation of G2/M checkpoint arrest, was noted in FaDu cells at this timepoint. These results suggest that alterations of chk1 signaling are associated with the response to topoisomerase I poison SN-38. Furthermore, A253 cells possess higher levels of endogenous hMLH1, compared to FaDu cells. A deficiency in G2 arrest was observed in FaDu cells, suggesting endogenous hMLH1 protein expression is associated with the abrogation of G2/M arrest, subsequently with the response to topoisomerase I poison SN-38.
Gunnar Hapke; Ming-Biao Yin; Jiaxi Wu; Cheryl Frank; Youcef M Rustum
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  International journal of oncology     Volume:  21     ISSN:  1019-6439     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2002 Nov 
Date Detail:
Created Date:  2002-10-08     Completed Date:  2003-03-04     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  1059-66     Citation Subset:  IM    
Department of Pharmacology and Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
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MeSH Terms
14-3-3 Proteins
Adaptor Proteins, Signal Transducing
Antineoplastic Agents, Phytogenic / pharmacology*
Camptothecin / analogs & derivatives*,  pharmacology*
Carrier Proteins
Cell Cycle Proteins / analysis
DNA Damage
DNA Fragmentation / drug effects
DNA-Binding Proteins*
Enzyme Inhibitors / pharmacology*
G2 Phase / drug effects
Head and Neck Neoplasms / drug therapy*,  metabolism,  pathology
MutS Homolog 2 Protein
Neoplasm Proteins / analysis
Nuclear Proteins
Protein Kinases / metabolism*
Proto-Oncogene Proteins / analysis
Serine / metabolism*
Topoisomerase I Inhibitors*
Tumor Cells, Cultured
Tyrosine 3-Monooxygenase / analysis
cdc25 Phosphatases / analysis
Grant Support
Reg. No./Substance:
0/14-3-3 Proteins; 0/Adaptor Proteins, Signal Transducing; 0/Antineoplastic Agents, Phytogenic; 0/Carrier Proteins; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Enzyme Inhibitors; 0/MLH1 protein, human; 0/Neoplasm Proteins; 0/Nuclear Proteins; 0/Proto-Oncogene Proteins; 0/Topoisomerase I Inhibitors; 100286-90-6/irinotecan; 56-45-1/Serine; 7689-03-4/Camptothecin; EC 3-Monooxygenase; EC 2.7.-/Protein Kinases; EC kinase 1; EC protein, human; EC Phosphatases; EC protein, human; EC Homolog 2 Protein

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