文章基本信息

标题：Landscape and flux reveal a new global view and physical quantification of mammalian cell cycle
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作者：Chunhe Li ; Jin Wang
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：39
页码：14130-14135
DOI：10.1073/pnas.1408628111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceUnderstanding the mechanisms of the cell cycle remains challenging. The cell cycle is regulated by the underlying gene regulatory networks. We uncovered the underlying Mexican hat landscape of a mammalian cell cycle network. Three local basins of attraction along the cell cycle loop emerge, corresponding to three distinct cell cycle states: the G1, S/G2, and M phases. Two barriers along the loop characterize G1 and S/G2 checkpoints, respectively, of the cell cycle, which provide a physical explanation for cell cycle checkpoint mechanisms. The cell cycle is determined by two driving forces: curl flux and potential barriers. We uncovered the key gene regulations determining the progression of cell cycle, which can be used to guide the design of new anticancer tactics. Cell cycles, essential for biological function, have been investigated extensively. However, enabling a global understanding and defining a physical quantification of the stability and function of the cell cycle remains challenging. Based upon a mammalian cell cycle gene network, we uncovered the underlying Mexican hat landscape of the cell cycle. We found the emergence of three local basins of attraction and two major potential barriers along the cell cycle trajectory. The three local basins of attraction characterize the G1, S/G2, and M phases. The barriers characterize the G1 and S/G2 checkpoints, respectively, of the cell cycle, thus providing an explanation of the checkpoint mechanism for the cell cycle from the physical perspective. We found that the progression of a cell cycle is determined by two driving forces: curl flux for acceleration and potential barriers for deceleration along the cycle path. Therefore, the cell cycle can be promoted (suppressed), either by enhancing (suppressing) the flux (representing the energy input) or by lowering (increasing) the barrier along the cell cycle path. We found that both the entropy production rate and energy per cell cycle increase as the growth factor increases. This reflects that cell growth and division are driven by energy or nutrition supply. More energy input increases flux and decreases barrier along the cell cycle path, leading to faster oscillations. We also identified certain key genes and regulations for stability and progression of the cell cycle. Some of these findings were evidenced from experiments whereas others lead to predictions and potential anticancer strategies.
关键词：cell cycle phases ; cell cycle checkpoints ; landscape ; flux