Bcl-2蛋白抑制钙信号的建模与全局动力学分析

牛帅; 帅建伟; 祁宏

doi:10.7498/aps.66.238701

摘要

钙离子（Ca2+）是生物体内一种“生死攸关”的信号分子，Bcl-2蛋白可以直接或间接调节IP3R通道释放Ca2+的能力，借此决定细胞命运.本文基于新近的实验成果，针对Bcl-2蛋白间接调控Ca2+的信号通路建立数学模型，得到了与实验数据相符合的结果，从理论上证明了Bcl-2蛋白对钙信号有抑制作用.在对模型进行鲁棒性检验之后，本文对该信号通路中一些关键组分的作用进行了预测.以[IP3]和[Bcl-2]为双分岔参数分析的结果表明Bcl-2对刺激强度能产生Ca2+振荡的区域有重要影响.以蛋白磷酸酶1[PP1]和蛋白激酶A[PKA]为单分岔参数分析的结果揭示：PP1可以有效地抑制钙信号，而PKA对钙信号的促进作用有一定的局限性.模型结果表明，不同浓度组合的IP3，Bcl-2和PKA会对钙信号发挥复杂的调控作用.本文不仅对相关生物学实验有一定的指导作用，而且可为治疗因钙信号失调而导致的疾病提供思路.

关键词:

Bcl-2蛋白 /
钙信号 /
分岔分析

Abstract

Calcium ion (Ca2+) is a signal for both life and death in cells. Either directly or indirectly, Bcl-2 protein can regulate Ca2+ release from IP3R channel, thereby determining the cell fate. In this work, based on recent experimental results, a mathematical model is constructed to describe the signaling pathway of Ca2+ release regulated by Bcl-2 indirectly. The model output fits nicely to the experimental data. The model demonstrates that Bcl-2 can suppress Ca2+ signaling. After the robustness test of the model, the roles of some key components in the signaling pathway are predicted. Two-parameter bifurcation analyses of[IP3] and [Bcl-2] are conducted to show that Bcl-2 has a crucial role in the oscillatory region of Ca2+ signaling. Single-parameter bifurcation analyses of [PP1] and [PKA] reveal that the PP1 can inhibit Ca2+ from signaling potently, while PKA only promotes Ca2+ signaling to some extent. Our model also indicates that the different combinations of concentrations of IP3, Bcl-2 and PKA generate complex regulations on Ca2+ signaling. This work not only plays a guiding role in relevant biological experiments, but also provides some insights into the treatment of diseases caused by disruption of Ca2+ homeostasis.

Keywords:

作者及机构信息

1.
山西大学复杂系统研究所, 太原 030006;

2.
山西大学数学科学学院, 太原 030006;

3.
厦门大学物理系, 厦门 361005

通信作者: 帅建伟, jianweishuai@xmu.edu.cn;hongqi@sxu.edu.cn ; 祁宏, jianweishuai@xmu.edu.cn;hongqi@sxu.edu.cn

基金项目: 国家自然科学基金（批准号：11504214，31370830，11675134）资助的课题.

Authors and contacts

1.
Complex Systems Research Center, Shanxi University, Taiyuan 030006, China;

2.
School of Mathematical Sciences, Shanxi University, Taiyuan 030006, China;

3.
Department of Physics, Xiamen University, Xiamen 361005, China

Corresponding author: Shuai Jian-Wei, jianweishuai@xmu.edu.cn;hongqi@sxu.edu.cn ; Qi Hong, jianweishuai@xmu.edu.cn;hongqi@sxu.edu.cn

Funds: Project supported by the National Natural Science Foundation of China (Grant Nos. 11504214, 31370830, 11675134).

参考文献

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[40]	Giorgi C, Bonora M, Sorrentino G, Missiroli S, Poletti F, Suski J M, Ramirez F G, Rizzuto R, Di Virgilio F, Zito E 2015 Proc. Natl. Acad. Sci. USA 112 1779
[41]	Roderick H L, Cook S J 2008 Nat. Rev. Cancer 8 361
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施引文献

[1]	Berridge M J, Bootman M D, Roderick H L 2003 Nat. Rev. Mol. Cell Biol. 4 517
[2]	Orrenius S, Zhivotovsky B, Nicotera P 2003 Nat. Rev. Mol. Cell Biol. 4 552
[3]	Parekh A B 2011 Trends Biochem. Sci. 36 78
[4]	Gerasimenko J V, Gerasimenko O V, Palejwala A, Tepikin A V, Petersen O H, Watson A J 2002 J. Cell Sci. 115 485
[5]	Scorrano L, Oakes S A, Opferman J T, Cheng E H, Sorcinelli M D, Pozzan T, Korsmeyer S J 2003 Science 300 135
[6]	Florea A M, Splettstoesser F, Dopp E, Rettenmeier A W, Bsselberg D 2005 Toxicology 216 1
[7]	Boehning D, Patterson R L, Sedaghat L, Glebova N O, Kurosaki T, Snyder S H 2003 Nat. Cell Biol. 5 1051
[8]	Piacentini R, Gangitano C, Ceccariglia S, Fà A D, Azzena G B, Michetti F, Grassi C 2008 J. Neurochem. 105 2109
[9]	Kim I, Xu W, Reed J C 2008 Nat. Rev. Drug Discov. 7 1013
[10]	Qi H, Shuai J W 2016 Med. Hypotheses 89 28
[11]	Prole D L, Taylor C W 2016 J. Physiol. 594 2849
[12]	Foskett J K, White C, Cheung K H, Mak D O D 2007 Physiol. Rev. 87 593
[13]	Vervliet T, Parys J, Bultynck G 2016 Oncogene 35 5079
[14]	Rong Y P, Bultynck G, Aromolaran A S, Zhong F, Parys J B, de Smedt H, Mignery G A, Roderick H L, Bootman M D, Distelhorst C W 2009 Proc. Natl. Acad. Sci. USA 106 14397
[15]	Chang M J, Zhong F, Lavik A R, Parys J B, Berridge M J, Distelhorst C W 2014 Proc. Natl. Acad. Sci. USA 111 1186
[16]	Lu B Y, Yue H 2010 Acta Biophys. Sin. 26 406 (in Chinese)[鲁保云, 岳红 2010 生物 26 406]
[17]	Li X, Liu F, Shuai J W (in Chinese)[李翔, 刘锋, 帅建伟 2016 65 178704]
[18]	Li Y X, Rinzel J 1994 J. Theor. Biol. 166 461
[19]	Ferrell J E, Ha S H 2014 Trends Biochem. Sci. 39 496
[20]	Li H, Rao A, Hogan P G 2011 Trends Cell Biol. 21 91
[21]	Yi M, Zhao Q, Tang J, Wang C 2011 Biophys. Chem. 157 33
[22]	Goldbeter A 1991 Proc. Natl. Acad. Sci. USA 88 9107
[23]	Parys J, Bezprozvanny I 1995 Cell Calcium 18 353
[24]	Svenningsson P, Nishi A, Fisone G, Girault J A, Nairn A C, Greengard P 2004 Annu. Rev. Pharmacol. Toxicol. 44 269
[25]	Shin S Y, Choo S M, Kim D, Baek S J, Wolkenhauer O, Cho K H 2006 FEBS Lett. 580 5965
[26]	Neves S R, Tsokas P, Sarkar A, Grace E A, Rangamani P, Taubenfeld S M, Alberini C M, Schaff J C, Blitzer R D, Moraru I I 2008 Cell 133 666
[27]	Lindner A U, Prehn J H, Huber H J 2013 Mol. Biosyst. 9 2359
[28]	Alzayady K J, Wang L, Chandrasekhar R, Wagner L E 2016 Sci. Signal. 9 ra35
[29]	De Young G W, Keizer J 1992 Proc. Natl. Acad. Sci. USA 89 9895
[30]	Shuai J W, Jung P 2003 Proc. Natl. Acad. Sci. USA 100 506
[31]	Qi H, Li L X, Shuai J W 2015 Sci. Rep. 5 7984
[32]	Sneyd J, Han J M, Wang L, Chen J, Yang X, Tanimura A, Sanderson M J, Kirk V, Yule D I 2017 Proc. Natl. Acad. Sci. USA 114 1456
[33]	Alon U 2007 Nat. Rev. Genet. 8 450
[34]	Dyachok O, Gylfe E 2004 J. Biol. Chem. 279 45455
[35]	Chaloux B, Caron A Z, Guillemette G 2007 Biol. Cell 99 379
[36]	Ceulemans H, Bollen M 2004 Physiol. Rev. 84 1
[37]	Bononi A, Agnoletto C, de Marchi E, Marchi S, Patergnani S, Bonora M, Giorgi C, Missiroli S, Poletti F, Rimessi A, Pinton P 2011 Enzym. Res. 2011 329098
[38]	Tang T S, Tu H P, Wang Z N, Bezprozvanny I 2003 J. Neurosci. 23 403
[39]	Luna-Vargas M P, Chipuk J E 2016 Trends Cell Biol. 26 906
[40]	Giorgi C, Bonora M, Sorrentino G, Missiroli S, Poletti F, Suski J M, Ramirez F G, Rizzuto R, Di Virgilio F, Zito E 2015 Proc. Natl. Acad. Sci. USA 112 1779
[41]	Roderick H L, Cook S J 2008 Nat. Rev. Cancer 8 361
[42]	Monteith G R, Prevarskaya N, Roberts-Thomson S J 2017 Nat. Rev. Cancer. 17 367

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