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Bhonde, M.R.* ; Hanski, M.L.* ; Budczies, J. ; Cao, M.* ; Gillissen, B.* ; Moorthy, D.* ; Simonetta, F.* ; Scherübl, H.* ; Truss, M.* ; Hagemeier, C.* ; Mewes, H.-W. ; Daniel, P.T.* ; Zeitz, M.* ; Hanski, C.*

DNA damage-induced expression of p53 suppresses mitotic checkpoint kinase hMps1.

J. Biol. Chem. 281, 8675-8685 (2006)
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DNA damage induced by the topoisomerase I inhibitor irinotecan (CPT-11) triggers in p53WT colorectal carcinoma cells a long term cell cycle arrest and in p53MUT cells a transient arrest followed by apoptosis (Magrini, R., Bhonde, M. R., Hanski, M. L., Notter, M., Scherübl, H., Boland, C. R., Zeitz, M., and Hanski, C. (2002) Int. J. Cancer 101, 23-31; Bhonde, M. R., Hanski, M. L., Notter, M., Gillissen, B. F., Daniel, P. T., Zeitz, M., and Hanski, C. (2006) Oncogene 25, 165-175). The mechanism of the p53-independent apoptosis still remains largely unclear. Here we used five p53WT and five p53MUT established colon carcinoma cell lines to identify gene expression alterations associated with apoptosis in p53MUT cells after treatment with SN-38, the irinotecan metabolite. After treatment, 16 mitosis-related genes were found to be expressed at least 2-fold stronger in the apoptosis-executing p53MUT cells than in the cell cycle-arrested p53WT cells by oligonucleotide microarray analysis. One of the genes whose strong post-treatment expression was associated with apoptosis was the mitotic checkpoint kinase hMps1 (human ortholog of the yeast monopolar spindle 1 kinase). hMps1 mRNA and protein expression were suppressed by the treatment-induced and by the exogenous adenovirus-coded p53 protein. The direct suppression of hMps1 on RNA level or inhibition of its activity by a dominant-negative hMps1 partly suppressed apoptosis. Together, these data indicate that the high expression of mitotic genes in p53 MUT cells after SN-38 treatment contributes to DNA damage-induced apoptosis, whereas their suppression in p53WT cells acts as a safeguard mechanism preventing mitosis initiation and the subsequent apoptosis. hMps1 kinase is one of the mitotic checkpoint proteins whose expression after DNA damage in p53 MUT cells activates the checkpoint and contributes to apoptosis. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
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Publication type Article: Journal article
Document type Scientific Article
Language english
Publication Year 2006
HGF-reported in Year 0
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Journal Journal of Biological Chemistry, The
Quellenangaben Volume: 281, Issue: 13, Pages: 8675-8685 Article Number: , Supplement: ,
Publisher American Society for Biochemistry and Molecular Biology
Reviewing status Peer reviewed
Institute(s) Institute of Bioinformatics and Systems Biology (IBIS)
POF-Topic(s) 30505 - New Technologies for Biomedical Discoveries
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503700-001
DOI 10.1074/jbc.M511333200
Scopus ID 33646843583
Erfassungsdatum 2006-11-07
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