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
Source PublicationJOURNAL OF THEORETICAL BIOLOGY
ISSN0022-5193
Volume462Pages:134-147
Status已发表
DOI10.1016/j.jtbi.2018.11.008
AbstractThe 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.
Keywordp53 Apoptosis Mathematical modelling DNA Damage response Apoptotic switch
Indexed BySCI
Language英语
Funding ProjectMinistry 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 Research AreaLife Sciences & Biomedicine - Other Topics ; Mathematical & Computational Biology
WOS SubjectBiology ; Mathematical & Computational Biology
WOS IDWOS:000455972600010
PublisherACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
WOS KeywordCELL FATE DECISION ; NF-KAPPA-B ; CYCLE PROGRESSION ; BASAL DYNAMICS ; CYTOCHROME-C ; CANCER-CELLS ; PUMA ; LIFE ; FAMILY ; DEATH
Original Document TypeArticle
Citation statistics
Cited Times:4[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttps://kms.shanghaitech.edu.cn/handle/2MSLDSTB/29884
Collection信息科学与技术学院_PI研究组_郑杰组
信息科学与技术学院
Corresponding AuthorKulasiri, Don
Affiliation1.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
Recommended Citation
GB/T 7714
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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