A mathematical model of cellular apoptosis and senescence through the dynamics of telomere loss
A mathematical model of cellular apoptosis and senescence through the dynamics of telomere loss
复制标题
DOI：
10.1016/j.jtbi.2004.12.016
复制
发表时间：
2005-07-07
影响因子：
2
通讯作者：
Arkus, N
中科院分区：
文献类型：
--
作者：
Arkus, N
当细胞复制时端粒重复的缩短一直被认为是细胞活力的决定因素。然而，最近的研究表明，决定细胞是否经历凋亡（程序性细胞死亡）、进入衰老（静止、非复制状态）或继续增殖的不是端粒长度，而是端粒是否结合了端粒相关蛋白（在哺乳动物中是TTAGGG重复结合因子-2 (TRF2)）。当与端粒结合时，TRF2允许细胞将端粒识别为染色体的终点，而不是DNA的断裂点。当端粒不与TRF2结合时，细胞要么通过DNA损伤反应途径立即触发衰老或凋亡，要么通过试图修复染色体间接触发衰老或凋亡，从而导致染色体末端连接。我们将端粒结合TRF2的能力作为端粒长度的函数进行建模，并将由此产生的结合概率应用于假设均匀细胞群的细胞复制模型。该模型与培养的人成纤维细胞和人胚胎肾细胞的两个自由参数拟合良好。我们提取细胞增殖停止时端粒损失百分比的值。我们表明，与先前的实验一致，TRF2的过表达允许细胞延迟衰老设定值。我们探讨了氧化应激对细胞活力的影响，氧化应激增加了端粒的损耗率，并表明细胞在氧化应激的存在下寿命缩短。我们还表明，端粒酶（一种维持端粒长度的酶）的加入足以导致细胞不朽。我们的结论是，随着端粒的缩短，TRF2结合端粒的能力越来越弱，这是细胞凋亡或衰老的一个定量合理的模型。(c) 2005年Elsevier Ltd出版
The shortening of telomeric repeats as a cell replicates has long been implicated as a determinant of cell viability. However, recent studies have indicated that it is not telomere length, but rather whether telomeres have bound a telomere-related protein, which in mammals is TTAGGG repeat binding factor-2 (TRF2), that determines whether a cell undergoes apoptosis (programmed cell death), enters senescence (a quiescent, non-replicative state), or continues to proliferate. When bound to a telomere, TRF2 allows a cell to recognize the telomere as the point where a chromosome ends rather than a break in DNA. When telomeres are not bound by TRF2, the cell can either immediately trigger senescence or apoptosis via the DNA damage response pathway, or indirectly trigger it by attempting to repair the chromosome, which results in chromosomal end joining. We model the ability of telomeres to bind TRF2 as a function of telomere length and apply the resulting binding probability to a model of cellular replication that assumes a homogeneous cell population. The model fits data from cultured human fibroblasts and human embryonic kidney cells for two free parameters well. We extract values for the percent of telomere loss at which cell proliferation ceases. We show, in agreement with previous experiments, that overexpression of TRF2 allows a cell to delay the senescence setpoint. We explore the effect of oxidative stress, which increases the rate of telomere loss, on cell viability and show that cells in the presence of oxidative stress have reduced lifespans. We also show that the addition of telomerase, an enzyme that maintains telomere length, is sufficient to result in cell immortality. We conclude that the increasing inability of TRF2 to bind telomeres as they shorten is a quantitatively reasonable model for a cause of either cellular apoptosis or senescence. (c) 2005 Published by Elsevier Ltd.