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Modeling the role of p53 pulses in DNA damage- induced cell death decision.

Sun T, Chen C, Wu Y, Zhang S, Cui J, Shen P - BMC Bioinformatics (2009)

Bottom Line: Further computational analyses indicated that p53-dependent PUMA accumulation and the PUMA-controlled Bax activation switch might play pivotal roles to count p53 pulses and thus decide the cell fate.Meanwhile, the Bax activation switch can count p53 pulses through PUMA accumulation and transfer it into death signal.Our modeling provides a plausible mechanism about how cells generate and orchestrate p53 pulses to tip the balance between survival and death.

View Article: PubMed Central - HTML - PubMed

Affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, PR China. confucian007@126.com

ABSTRACT

Background: The tumor suppressor p53 plays pivotal roles in tumorigenesis suppression. Although oscillations of p53 have been extensively studied, the mechanism of p53 pulses and their physiological roles in DNA damage response remain unclear.

Results: To address these questions we presented an integrated model in which Ataxia-Telangiectasia Mutated (ATM) activation and p53 oscillation were incorporated with downstream apoptotic events, particularly the interplays between Bcl-2 family proteins. We first reproduced digital oscillation of p53 as the response of normal cells to DNA damage. Subsequent modeling in mutant cells showed that high basal DNA damage is a plausible cause for sustained p53 pulses observed in tumor cells. Further computational analyses indicated that p53-dependent PUMA accumulation and the PUMA-controlled Bax activation switch might play pivotal roles to count p53 pulses and thus decide the cell fate.

Conclusion: The high levels of basal DNA damage are responsible for generating sustained pulses of p53 in the tumor cells. Meanwhile, the Bax activation switch can count p53 pulses through PUMA accumulation and transfer it into death signal. Our modeling provides a plausible mechanism about how cells generate and orchestrate p53 pulses to tip the balance between survival and death.

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Related in: MedlinePlus

Schematic Representation of the regulatory network. Three modules are represented in corresponding dotted Box. I: ATM module. This module delineates ATM activation through both MRN mediated process and autophosphorylation. II: p53-MDM2 module. The tumor suppressor p53 participates in DNA breaks repair process in multiple ways and also induces PUMA expression which functions as 'input signals' to the downstream Bax activation switch. III: Bax activation switch module. Pro-apoptotic members of Bcl2 family termed 'BH3-only' proteins either dissociates Bax/Bak from the sequestration of anti-death members (enabler) or directly activates Bax/Bak (activator). PUMA serves as 'enabler' and is p53 inducible. PUMA functions as 'input' to the downstream Bax activation module. Dotted lines donate regulatory control and solid lines represent mass flow. Arrow means activation, horizontal bar means inhibition. 'Φ' donates degradation.
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Figure 1: Schematic Representation of the regulatory network. Three modules are represented in corresponding dotted Box. I: ATM module. This module delineates ATM activation through both MRN mediated process and autophosphorylation. II: p53-MDM2 module. The tumor suppressor p53 participates in DNA breaks repair process in multiple ways and also induces PUMA expression which functions as 'input signals' to the downstream Bax activation switch. III: Bax activation switch module. Pro-apoptotic members of Bcl2 family termed 'BH3-only' proteins either dissociates Bax/Bak from the sequestration of anti-death members (enabler) or directly activates Bax/Bak (activator). PUMA serves as 'enabler' and is p53 inducible. PUMA functions as 'input' to the downstream Bax activation module. Dotted lines donate regulatory control and solid lines represent mass flow. Arrow means activation, horizontal bar means inhibition. 'Φ' donates degradation.

Mentions: Our models are based on established biological facts and supplemented by some assumptions and simplifications. The schematic representation of p53 network is given in Figure 1. The details and necessary model simplifications are described in "Methods". The model can be further dissected into three functionally connected sub-modules, the interconnections of which are based on the input-out patterns (See Figure 1 for details). We then investigated the bifurcation properties of each function module.


Modeling the role of p53 pulses in DNA damage- induced cell death decision.

Sun T, Chen C, Wu Y, Zhang S, Cui J, Shen P - BMC Bioinformatics (2009)

Schematic Representation of the regulatory network. Three modules are represented in corresponding dotted Box. I: ATM module. This module delineates ATM activation through both MRN mediated process and autophosphorylation. II: p53-MDM2 module. The tumor suppressor p53 participates in DNA breaks repair process in multiple ways and also induces PUMA expression which functions as 'input signals' to the downstream Bax activation switch. III: Bax activation switch module. Pro-apoptotic members of Bcl2 family termed 'BH3-only' proteins either dissociates Bax/Bak from the sequestration of anti-death members (enabler) or directly activates Bax/Bak (activator). PUMA serves as 'enabler' and is p53 inducible. PUMA functions as 'input' to the downstream Bax activation module. Dotted lines donate regulatory control and solid lines represent mass flow. Arrow means activation, horizontal bar means inhibition. 'Φ' donates degradation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2713228&req=5

Figure 1: Schematic Representation of the regulatory network. Three modules are represented in corresponding dotted Box. I: ATM module. This module delineates ATM activation through both MRN mediated process and autophosphorylation. II: p53-MDM2 module. The tumor suppressor p53 participates in DNA breaks repair process in multiple ways and also induces PUMA expression which functions as 'input signals' to the downstream Bax activation switch. III: Bax activation switch module. Pro-apoptotic members of Bcl2 family termed 'BH3-only' proteins either dissociates Bax/Bak from the sequestration of anti-death members (enabler) or directly activates Bax/Bak (activator). PUMA serves as 'enabler' and is p53 inducible. PUMA functions as 'input' to the downstream Bax activation module. Dotted lines donate regulatory control and solid lines represent mass flow. Arrow means activation, horizontal bar means inhibition. 'Φ' donates degradation.
Mentions: Our models are based on established biological facts and supplemented by some assumptions and simplifications. The schematic representation of p53 network is given in Figure 1. The details and necessary model simplifications are described in "Methods". The model can be further dissected into three functionally connected sub-modules, the interconnections of which are based on the input-out patterns (See Figure 1 for details). We then investigated the bifurcation properties of each function module.

Bottom Line: Further computational analyses indicated that p53-dependent PUMA accumulation and the PUMA-controlled Bax activation switch might play pivotal roles to count p53 pulses and thus decide the cell fate.Meanwhile, the Bax activation switch can count p53 pulses through PUMA accumulation and transfer it into death signal.Our modeling provides a plausible mechanism about how cells generate and orchestrate p53 pulses to tip the balance between survival and death.

View Article: PubMed Central - HTML - PubMed

Affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, PR China. confucian007@126.com

ABSTRACT

Background: The tumor suppressor p53 plays pivotal roles in tumorigenesis suppression. Although oscillations of p53 have been extensively studied, the mechanism of p53 pulses and their physiological roles in DNA damage response remain unclear.

Results: To address these questions we presented an integrated model in which Ataxia-Telangiectasia Mutated (ATM) activation and p53 oscillation were incorporated with downstream apoptotic events, particularly the interplays between Bcl-2 family proteins. We first reproduced digital oscillation of p53 as the response of normal cells to DNA damage. Subsequent modeling in mutant cells showed that high basal DNA damage is a plausible cause for sustained p53 pulses observed in tumor cells. Further computational analyses indicated that p53-dependent PUMA accumulation and the PUMA-controlled Bax activation switch might play pivotal roles to count p53 pulses and thus decide the cell fate.

Conclusion: The high levels of basal DNA damage are responsible for generating sustained pulses of p53 in the tumor cells. Meanwhile, the Bax activation switch can count p53 pulses through PUMA accumulation and transfer it into death signal. Our modeling provides a plausible mechanism about how cells generate and orchestrate p53 pulses to tip the balance between survival and death.

Show MeSH
Related in: MedlinePlus