Mdm2生成速率调控的p53-Mdm2振子的全局动力学和稳定性

毕远宏; 杨卓琴; 何小燕

doi:10.7498/aps.65.028701

摘要

肿瘤抑制蛋白p53的动力学在一定程度上可以决定DNA损伤后的细胞命运. p53 的动力学行为与p53信号通路中p53-Mdm2振子模块密切相关. 然而, p53的负调控子Mdm2 的生成速率的增加使其在一些癌细胞中过表达. 因此探讨Mdm2生成速率对p53动力学的影响有重要意义. 同时, PDCD5作为p53的激活子也调控p53的表达. 因此, 本文针对PDCD5调控的p53-Mdm2 振子模型, 通过分岔分析获得了Mdm2生成速率所调控的p53的单稳态、振荡以及单稳态与振荡共存的动力学行为, 且稳定性通过能量面进行了分析. 此外, 噪声强度对p53动力学的稳定性有重要的影响. 因此, 针对p53的振荡行为, 探讨了噪声强度对势垒高度和周期的影响. 本文所获得的结果对理解DNA损伤后的p53信号通路调控起到一定的指导作用.

关键词:

Abstract

Studying global dynamics and stability of biological network is of importance in order to understand its function and behavior. In this paper, we consider the p53-Mdm2 oscillator module with PDCD5 as a core part of p53 signaling pathway after the DNA damage, and explore the dynamics and stability of the tumor suppressor p53. The dynamics of p53 may decide the cell fate after the DNA damage, while the oscillation of p53 may induce cell cycle arrest and so promote the repair of DNA, and the high levels of p53 can trigger apoptosis. However, p53 activity may be inhibited by its negative regulator Mdm2 in some cancer cells, as Mdm2 is of overexpression due to the increase in Mdm2 production rate. So we first investigate the effect of Mdm2 production rate on the kinetics of p53 through bifurcation analysis. after the DNA damage. With the increase in Mdm2 production rate, p53 can display a steady state, a stable-limit cycle and the coexistence of a stable-limit cycle and a stable steady state. Furthermore, the potential landscapes for oscillation show that the lower concentration of p53 means a stronger stability, whereas those for bistability of the higher steady state and the oscillatory state illustrate that stability of the higher steady state increases with the increasing Mdm2 production rate. In addition, noise strength can greatly affect the stability of p53 oscillations, so we explore the effect of noise strength on potential landscapes, barrier heights and periods. A smaller noise strength leads to a higher barrier height associated with more stable-limit cycle, and the harmonic oscillation with more uniform period and smaller variance is helpful to have more stable maintainance. Our results may be useful for understanding regulation of p53 signaling pathway after DNA damage.

Keywords:

作者及机构信息

1.
北京航空航天大学数学与系统科学学院, 数学、信息与行为教育部重点实验室, 北京 100191;

2.
内蒙古财经大学统计与数学学院, 呼和浩特 010070

通信作者: 杨卓琴, yangzhuoqin@buaa.edu.cn

基金项目: 国家自然科学基金(批准号: 11372017, 11472009)和内蒙古自治区高等学校科学技术研究项目(批准号: NJZY14130)资助的课题.

Authors and contacts

1.
School of Mathematics and Systems Science and LMIB, Beihang University, Beijing 100191, China;

2.
School of Statistics and Mathematics, Inner Mongolia University of Finance and Economics, Hohhot 010070, China

Corresponding author: Yang Zhuo-Qin, yangzhuoqin@buaa.edu.cn

Funds: Project supported by the National Natural Science Foundation of China (Grant Nos. 11372017, 11472009), and the Research Program of Science and Technology at Universities of Inner Mongolia Autonomous Region, China (Grant No. NJZY14130).

参考文献

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[17]	Batchelor E, Mock C S, Bhan I, Loewer A, Lahav G 2008 Mol. Cell 30 277
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[20]	Wang J, Li C H, Wang E K 2010 Proc. Natl. Acad. Sci. U.S.A 107 8195
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[22]	Yan H, Zhao L, Hu L, Wang X D, Wang E K, Wang J 2013 Proc. Natl. Acad. Sci. U.S.A 110 E4185
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[24]	Rinaldo C, Prodosmo A, Mancini F, Iacovelli S, Sacchi A, Moretti F, Soddu S 2007 Mol. Cell 25 739

施引文献

[1]	Kubbutat M H G, Jones S N, Vousden K H 1997 Nature 387 299
[2]	Vousden K H, Lane D P 2007 Nat.Rev. Mol. Cell Biol. 8 275
[3]	Zhang X P, Liu F, Wang W 2012 Biophys. J. 102 2251
[4]	Zhang X P, Liu F, Cheng Z, Wang W 2009 Proc. Natl. Acad. Sci. U.S.A 106 12245
[5]	Zhang X P, Liu F, Wang W 2011 Proc. Natl. Acad. Sci. U.S.A 108 8990
[6]	Ashcroft M, Vousden K H 1999 Oncogene 18 7637
[7]	Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, Vassilev L T 2006 Proc. Natl. Acad. Sci. U.S.A 103 1888
[8]	Bose I, Ghosh B 2007 J. Biosci. 32 991
[9]	Zhang L J, Yan S W, Zhuo Y Z 2007 Acta Phys. Sin. 56 2442 (in Chinese) [张丽娟, 晏世伟, 卓益忠 2007 物理学报 56 2442]
[10]	Xia J F, Jia Y 2010 Chin. Phys. B 19 040506
[11]	Geng D Y, Xie H J, Wan X W, Xu G Z 2014 Acta Phys. Sin. 63 018702 (in Chinese) [耿读艳, 谢红娟, 万晓伟, 徐桂芝 2014 物理学报 63 018702]
[12]	Bakkenist C J, Kastan M B 2003 Nature 421 499
[13]	Stommel J M, Wahl G M 2004 EMBO J. 23 1547
[14]	Yin Y, Stephen C W, Luciani M G, Fahraeus R 2002 Nat. Cell Biol. 4 462
[15]	Xu L J, Hu J, Zhao Y B, Hu J, Xiao J, Wang Y M, Ma D, Chen Y Y 2012 Apoptosis 17 1235
[16]	Zhuge C J, Sun X J, Chen Y Y, Lei J Z 2015 arXiv:1503.08274v1 [q-bio.MN]
[17]	Batchelor E, Mock C S, Bhan I, Loewer A, Lahav G 2008 Mol. Cell 30 277
[18]	Frauenfelder H, Sligar S G, Wolynes P G 1991 Science 254 1598
[19]	Wang J, Xu L, Wang E K 2008 Proc. Natl. Acad. Sci. U.S.A 105 12271
[20]	Wang J, Li C H, Wang E K 2010 Proc. Natl. Acad. Sci. U.S.A 107 8195
[21]	Tay S, Hughey J J, Lee T K, Lipniacki T, Quake S R, Covert M W 2010 Nature 466 267
[22]	Yan H, Zhao L, Hu L, Wang X D, Wang E K, Wang J 2013 Proc. Natl. Acad. Sci. U.S.A 110 E4185
[23]	Cao Z, Wang W D 2015 Prog. Biochem. Biophys. 42 147 (in Chinese) [曹志, 王卫东 2015 生物化学与生物物理进展 42 147]
[24]	Rinaldo C, Prodosmo A, Mancini F, Iacovelli S, Sacchi A, Moretti F, Soddu S 2007 Mol. Cell 25 739

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