Abstract
Despite numerous studies on the tumor suppressor p53, a complete picture of its role in cell arrest and killing in G1, S and G2M phases after drug treatment is lacking. We tackled the analysis of the complexity of cell cycle effects combining the time-course measures with different techniques with the aid of a computer program simulating cell cycle progression. This mixed experimental-simulation approach enabled us to decode the dynamics of the cytostatic and cytotoxic responses to cisplatin and doxorubicin treatments in a p53-proficient colon carcinoma cell line (HCT-116) and in its p53-deficient counterpart. We achieved a separate evaluation of the activity of each cell cycle control and we connected these results with measures of p53 level in G1, S and G2M. We confirmed the action of p53 in all cell cycle phases, but also the presence of strong p53-independent cytostatic and cytotoxic activities exerted by both drugs. In G1 phase, p53 was responsible for a medium/long term block, distinct from the short-term block, which was p53-independent. The delay in traversing S phase was reduced by the presence of p53. In G2M phase, despite a strong p53-independent block, there was a weaker but more persistent p53-dependent block. At cytotoxic concentrations, p53-dependent and p53-independent cell death was observed. The former was poorly phase-specific, occurred earlier and exploited the apoptotic mechanism more than p53-independent death. Computer simulation produced a framework where previous partial and sometimes apparently contradictory observations of the p53-mediated effects could be reconciled and explained.
| Original language | English |
|---|---|
| Pages (from-to) | 943-950 |
| Number of pages | 8 |
| Journal | Cell Cycle |
| Volume | 6 |
| Issue number | 8 |
| Publication status | Published - Apr 15 2007 |
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Keywords
- Anticancer drugs
- Cell cycle
- Cell kinetics
- Cisplatin
- Doxorubicin
- Flow cytometry
- Mathematical models
- p53
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
The contribution of p53 in the dynamics of cell cycle response to DNA damage interpreted by a mathematical model. / Lupi, Monica; Matera, Giada; Natoli, Claudia; Colombo, Valentina; Ubezio, Paolo.
In: Cell Cycle, Vol. 6, No. 8, 15.04.2007, p. 943-950.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The contribution of p53 in the dynamics of cell cycle response to DNA damage interpreted by a mathematical model
AU - Lupi, Monica
AU - Matera, Giada
AU - Natoli, Claudia
AU - Colombo, Valentina
AU - Ubezio, Paolo
PY - 2007/4/15
Y1 - 2007/4/15
N2 - Despite numerous studies on the tumor suppressor p53, a complete picture of its role in cell arrest and killing in G1, S and G2M phases after drug treatment is lacking. We tackled the analysis of the complexity of cell cycle effects combining the time-course measures with different techniques with the aid of a computer program simulating cell cycle progression. This mixed experimental-simulation approach enabled us to decode the dynamics of the cytostatic and cytotoxic responses to cisplatin and doxorubicin treatments in a p53-proficient colon carcinoma cell line (HCT-116) and in its p53-deficient counterpart. We achieved a separate evaluation of the activity of each cell cycle control and we connected these results with measures of p53 level in G1, S and G2M. We confirmed the action of p53 in all cell cycle phases, but also the presence of strong p53-independent cytostatic and cytotoxic activities exerted by both drugs. In G1 phase, p53 was responsible for a medium/long term block, distinct from the short-term block, which was p53-independent. The delay in traversing S phase was reduced by the presence of p53. In G2M phase, despite a strong p53-independent block, there was a weaker but more persistent p53-dependent block. At cytotoxic concentrations, p53-dependent and p53-independent cell death was observed. The former was poorly phase-specific, occurred earlier and exploited the apoptotic mechanism more than p53-independent death. Computer simulation produced a framework where previous partial and sometimes apparently contradictory observations of the p53-mediated effects could be reconciled and explained.
AB - Despite numerous studies on the tumor suppressor p53, a complete picture of its role in cell arrest and killing in G1, S and G2M phases after drug treatment is lacking. We tackled the analysis of the complexity of cell cycle effects combining the time-course measures with different techniques with the aid of a computer program simulating cell cycle progression. This mixed experimental-simulation approach enabled us to decode the dynamics of the cytostatic and cytotoxic responses to cisplatin and doxorubicin treatments in a p53-proficient colon carcinoma cell line (HCT-116) and in its p53-deficient counterpart. We achieved a separate evaluation of the activity of each cell cycle control and we connected these results with measures of p53 level in G1, S and G2M. We confirmed the action of p53 in all cell cycle phases, but also the presence of strong p53-independent cytostatic and cytotoxic activities exerted by both drugs. In G1 phase, p53 was responsible for a medium/long term block, distinct from the short-term block, which was p53-independent. The delay in traversing S phase was reduced by the presence of p53. In G2M phase, despite a strong p53-independent block, there was a weaker but more persistent p53-dependent block. At cytotoxic concentrations, p53-dependent and p53-independent cell death was observed. The former was poorly phase-specific, occurred earlier and exploited the apoptotic mechanism more than p53-independent death. Computer simulation produced a framework where previous partial and sometimes apparently contradictory observations of the p53-mediated effects could be reconciled and explained.
KW - Anticancer drugs
KW - Cell cycle
KW - Cell kinetics
KW - Cisplatin
KW - Doxorubicin
KW - Flow cytometry
KW - Mathematical models
KW - p53
UR - http://www.scopus.com/inward/record.url?scp=34247518636&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247518636&partnerID=8YFLogxK
M3 - Article
VL - 6
SP - 943
EP - 950
JO - Cell Cycle
JF - Cell Cycle
SN - 1538-4101
IS - 8
ER -