Negative feedback regulation of calcineurin-dependent Prz1 transcription factor by the CaMKK-CaMK1 axis in fission yeast.
Negative feedback regulation of calcineurin-dependent Prz1 transcription factor by the CaMKK-CaMK1 axis in fission yeast.
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DOI：
10.1093/nar/gku684
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发表时间：
2014-09
影响因子：
14.9
通讯作者：
Aligue R
中科院分区：
文献类型：
--
作者：
Cisneros-Barroso E;Yance-Chávez T;Kito A;Sugiura R;Gómez-Hierro A;Giménez-Zaragoza D;Aligue R
钙信号触发Prz1转录因子从细胞质到细胞核的转位。这一过程由钙激活的磷酸酶钙调神经磷酸酶调节，钙调神经磷酸酶激活Prz1，从而在钙信号转导过程中维持活跃的转录。当钙信号停止时，Prz1被磷酸化失活并输出到细胞质中。在萌芽中的酵母和哺乳动物细胞中，已有报道称不同的激酶可以对抗钙调神经磷酸酶的活性并调节核输出。在这里，我们证明了钙/钙调蛋白依赖的激酶Cmk1首先被新发现的激酶CAMKK2同系物Ckk2磷酸化并被激活，以响应钙离子。然后，活性的Cmk1结合、磷酸化和失活Prz1的转录活性，同时Prz1对钙离子的反应增强了cmk1的表达。此外，CDC25磷酸酶也被Cmk1磷酸化，导致细胞周期停滞，以响应钙离子的增加。此外，由于缺乏细胞周期抑制和Prz1活性升高，cmk1缺失显示出对长期暴露于钙离子的高耐受性。这项工作揭示了由新发现的Ckk2激活的Cmk1激酶通过负性调节Prz1的活性来抵消钙调神经磷酸酶的功能，而Prz1的活性反过来又参与激活cmk1基因的转录。这些结果是对裂殖酵母Cmk1和Ckk2功能的首次深入研究。
Calcium signals trigger the translocation of the Prz1 transcription factor from the cytoplasm to the nucleus. The process is regulated by the calcium-activated phosphatase calcineurin, which activates Prz1 thereby maintaining active transcription during calcium signalling. When calcium signalling ceases, Prz1 is inactivated by phosphorylation and exported to the cytoplasm. In budding yeast and mammalian cells, different kinases have been reported to counter calcineurin activity and regulate nuclear export. Here, we show that the Ca2+/calmodulin-dependent kinase Cmk1 is first phosphorylated and activated by the newly identified kinase CaMKK2 homologue, Ckk2, in response to Ca2+. Then, active Cmk1 binds, phosphorylates and inactivates Prz1 transcription activity whilst at the same time cmk1 expression is enhanced by Prz1 in response to Ca2+. Furthermore, Cdc25 phosphatase is also phosphorylated by Cmk1, inducing cell cycle arrest in response to an increase in Ca2+. Moreover, cmk1 deletion shows a high tolerance to chronic exposure to Ca2+, due to the lack of cell cycle inhibition and elevated Prz1 activity. This work reveals that Cmk1 kinase activated by the newly identified Ckk2 counteracts calcineurin function by negatively regulating Prz1 activity which in turn is involved in activating cmk1 gene transcription. These results are the first insights into Cmk1 and Ckk2 function in Schizosaccharomyces pombe.
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