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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.
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Keywords:
- Bcl-2 protein /
- calcium signaling /
- bifurcation analysis
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[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
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[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
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[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 生物物理学报 26 406]
[17] Li X, Liu F, Shuai J W (in Chinese)[李翔, 刘锋, 帅建伟 2016 物理学报 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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