Hcm1 integrates signals from Cdk1 and calcineurin to control cell proliferation.
Hcm1 integrates signals from Cdk1 and calcineurin to control cell proliferation.
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DOI：
10.1091/mbc.e15-07-0469
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发表时间：
2015-10-15
影响因子：
3.3
通讯作者：
Benanti JA
中科院分区：
文献类型：
--
作者：
Arsenault HE;Roy J;Mapa CE;Cyert MS;Benanti JA
转录因子Hcm1是染色体分离和基因组稳定性的关键调控因子。磷酸酶钙调磷酸酶在环境胁迫下直接使Hcm1失活，从而抑制增殖。Hcm1具有变阻器的功能，其磷酸化状态影响增殖速率。细胞周期蛋白依赖性激酶（Cdk1）通过协调细胞周期调节因子的活动来协调细胞周期的进程。尽管对抗Cdk1的磷酸酶可能是建立动态磷酸化所必需的，但针对大多数Cdk1底物的特异性磷酸酶尚未确定。在出芽酵母中，转录因子Hcm1激活调节染色体分离的基因表达，对维持基因组稳定性至关重要。以前我们发现Hcm1活性和降解是由Cdk1不同位点的磷酸化刺激的。在这里，我们表明，在暴露于环境压力下，磷酸酶钙调磷酸酶通过特异性地去除活化磷酸化来抑制Hcm1，并且这种调节对于细胞在遇到压力时延迟增殖是重要的。我们的工作确定了一种机制，通过该机制Cdk1的增殖信号在应激反应中被移除，并表明Hcm1作为一种变阻器，整合刺激和抑制信号来控制细胞增殖。
The transcription factor Hcm1 is a key regulator of chromosome segregation and genome stability. The phosphatase calcineurin directly inactivates Hcm1 in response to environmental stress, which inhibits proliferation. Hcm1 functions as a rheostat, whose phosphorylation state affects the rate of proliferation. Cyclin-dependent kinase (Cdk1) orchestrates progression through the cell cycle by coordinating the activities of cell-cycle regulators. Although phosphatases that oppose Cdk1 are likely to be necessary to establish dynamic phosphorylation, specific phosphatases that target most Cdk1 substrates have not been identified. In budding yeast, the transcription factor Hcm1 activates expression of genes that regulate chromosome segregation and is critical for maintaining genome stability. Previously we found that Hcm1 activity and degradation are stimulated by Cdk1 phosphorylation of distinct clusters of sites. Here we show that, upon exposure to environmental stress, the phosphatase calcineurin inhibits Hcm1 by specifically removing activating phosphorylations and that this regulation is important for cells to delay proliferation when they encounter stress. Our work identifies a mechanism by which proliferative signals from Cdk1 are removed in response to stress and suggests that Hcm1 functions as a rheostat that integrates stimulatory and inhibitory signals to control cell proliferation.