DNA damage-induced expression of p53 suppresses mitotic checkpoint kinase hMps1: the lack of this suppression in p53mut cells contributes to apoptosis.

@article{citeulike:488979, abstract = {DNA damage induced by the topoisomerase I inhibitor irinotecan (CPT-11) triggers in p53(wt) colorectal carcinoma cells a long-term cell cycle arrest and in p53(mut) cells a transient arrest followed by apoptosis (1,2). The mechanism of the p53-independent apoptosis still remains largely unclear. Here we used five p53(wt) and five p53(mut) 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 twofold stronger in the apoptosis-executing p53(mut) cells than in the cell cycle-arrested p53(wt) 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 was suppressed by the treatment-induced as well as 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 p53(wt) 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.}, address = {Dept. of Gastroenterology, Charite University Medical Center, Berlin 12200.}, author = {Bhonde, Mandar R R. and Hanski, Marie-Luise L. and Budczies, Jan and Cao, Minh and Gillissen, Bernd and Moorthy, Dhatchana and Simonetta, Federico and Scher\"{u}bl, Hans and Truss, Matthias and Hagemeier, Christian and Mewes, H W W. and Daniel, Peter T T. and Zeitz, Martin and Hanski, Christoph }, citeulike-article-id = {488979}, doi = {10.1074/jbc.M511333200}, issn = {0021-9258}, journal = {J Biol Chem}, keywords = {apoptosis, microarray}, month = {January}, posted-at = {2006-02-02 00:48:57}, priority = {2}, title = {DNA damage-induced expression of p53 suppresses mitotic checkpoint kinase hMps1: the lack of this suppression in p53mut cells contributes to apoptosis.}, url = {http://dx.doi.org/10.1074/jbc.M511333200}, year = {2006} }

TY - JOUR ID - citeulike:488979 L3 - citeulike-article-id:488979 TI - DNA damage-induced expression of p53 suppresses mitotic checkpoint kinase hMps1: the lack of this suppression in p53mut cells contributes to apoptosis. JF - J Biol Chem AD - Dept. of Gastroenterology, Charite University Medical Center, Berlin 12200. SN - 0021-9258 N2 - DNA damage induced by the topoisomerase I inhibitor irinotecan (CPT-11) triggers in p53(wt) colorectal carcinoma cells a long-term cell cycle arrest and in p53(mut) cells a transient arrest followed by apoptosis (1,2). The mechanism of the p53-independent apoptosis still remains largely unclear. Here we used five p53(wt) and five p53(mut) 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 twofold stronger in the apoptosis-executing p53(mut) cells than in the cell cycle-arrested p53(wt) 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 was suppressed by the treatment-induced as well as 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 p53(wt) 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. KW - apoptosis KW - microarray AU - Bhonde, Mandar R AU - Hanski, Marie-Luise AU - Budczies, Jan AU - Cao, Minh AU - Gillissen, Bernd AU - Moorthy, Dhatchana AU - Simonetta, Federico AU - Scherübl, Hans AU - Truss, Matthias AU - Hagemeier, Christian AU - Mewes, H W AU - Daniel, Peter T AU - Zeitz, Martin AU - Hanski, Christoph PY - 2006/01/30/ UR - http://dx.doi.org/10.1074/jbc.M511333200 ER -