Mathematical modelling of core regulatory mechanism in p53 protein that activates apoptotic switch
Chong, Ket Hing1; Samarasinghe, Sandhya2,3; Kulasiri, Don3,4; Zheng, Jie5
2019-02-07
发表期刊JOURNAL OF THEORETICAL BIOLOGY
ISSN0022-5193
卷号462页码:134-147
发表状态已发表
DOI10.1016/j.jtbi.2018.11.008
摘要The p53 protein, a tumour suppressor, is a key player in the DNA damage response. The activation of apoptosis by p53 involves the intrinsic apoptotic pathway to eliminate stressed cells that contain DNA lesions. Recent experiments have found that apoptosis happen in an all-or-none switch like manner (Al-beck et al., 2008; Rehm et al., 2002). We focus on modelling the mechanism of p53 activation of apoptosis in response to sustained high DNA double-strand breaks. The aim of the research is to investigate the design principles behind the regulation of p53 activation of apoptotic switch. Building on previous models (Chong et al., 2015; Zhang et al., 2009a), we developed a mathematical model that incorporated the molecular interactions in the core regulation of p53 and the apoptosis initiation module involving Puma, Bcl2 and Bax. Activation of Bax was assumed to be an indicator of apoptosis initiation. Chen et al. (2013) suggested that one of the components in the p53 pathway may control a threshold activation of apoptosis. We hypothesized that ATM auto-activation is the component that controls p53 threshold activation of apoptosis with ATM's multi-site autophosphorylation depending on damage intensity. The constructed model demonstrated how molecular interactions and stress signalling molecule ATM's auto-activation of the p53 network dictate cell fate decisions. Our simulation results are qualitatively consistent with the experimental findings of all-or-none activation of apoptosis and predicted overexpression of Bc12 as a factor in causing malfunction of the apoptotic switch. We present a simplified yet plausible model of molecular mechanism that controls p53 activation of apoptotic switch. (C) 2018 Elsevier Ltd. All rights reserved.
关键词p53 Apoptosis Mathematical modelling DNA Damage response Apoptotic switch
收录类别SCI ; SCIE
语种英语
资助项目Ministry of Education Singapore[RG120/15] ; Ministry of Education Singapore[2015-T1-002-094] ; Ministry of Education Singapore[ARC 39/13] ; Ministry of Education Singapore[MOE2013-T2-1-079]
WOS研究方向Life Sciences & Biomedicine - Other Topics ; Mathematical & Computational Biology
WOS类目Biology ; Mathematical & Computational Biology
WOS记录号WOS:000455972600010
出版者ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
WOS关键词CELL FATE DECISION ; NF-KAPPA-B ; CYCLE PROGRESSION ; BASAL DYNAMICS ; CYTOCHROME-C ; CANCER-CELLS ; PUMA ; LIFE ; FAMILY ; DEATH
原始文献类型Article
引用统计
文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/29884
专题信息科学与技术学院
信息科学与技术学院_PI研究组_郑杰组
通讯作者Kulasiri, Don
作者单位1.Nanyang Technol Univ, Sch Comp Sci & Engn, Biomed Informat Lab, Singapore 639798, Singapore
2.Lincoln Univ, Complex Syst Big Data & Informat Initiat CSBII, Christchurh, New Zealand
3.Lincoln Univ, Ctr Adv Computat Solut C FACS, Christchurh, New Zealand
4.Lincoln Univ, Dept Mol Biosci, Christchurh, New Zealand
5.ShanghaiTech Univ, Sch Informat Sci & Technol, Shanghai 201210, Peoples R China
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Chong, Ket Hing,Samarasinghe, Sandhya,Kulasiri, Don,et al. Mathematical modelling of core regulatory mechanism in p53 protein that activates apoptotic switch[J]. JOURNAL OF THEORETICAL BIOLOGY,2019,462:134-147.
APA Chong, Ket Hing,Samarasinghe, Sandhya,Kulasiri, Don,&Zheng, Jie.(2019).Mathematical modelling of core regulatory mechanism in p53 protein that activates apoptotic switch.JOURNAL OF THEORETICAL BIOLOGY,462,134-147.
MLA Chong, Ket Hing,et al."Mathematical modelling of core regulatory mechanism in p53 protein that activates apoptotic switch".JOURNAL OF THEORETICAL BIOLOGY 462(2019):134-147.
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