Functional overlap among distinct G1/S inhibitory pathways allows robust G1 arrest by yeast mating pheromones.
Functional overlap among distinct G1/S inhibitory pathways allows robust G1 arrest by yeast mating pheromones.
复制标题
不同 G1/S 抑制途径之间的功能重叠允许酵母交配信息素对 G1 进行强有力的抑制。
DOI：
10.1091/mbc.e13-07-0373
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发表时间：
2013
影响因子：
3.3
通讯作者：
Pryciak,PeterM
中科院分区：
文献类型：
--
作者：
Pope,PatriciaA;Pryciak,PeterM
在芽殖酵母中，交配信息素通过信息素激活的Cdk抑制剂（CKI）蛋白Far 1将细胞周期阻滞在G1期。然而，替代途径也必须存在，因为删除细胞周期蛋白CLN 2恢复了对far 1细胞的信息素阻滞。在这里，我们探测这些替代途径是否需要G1/S转录抑制Whi 5和Stb 1或CKI蛋白Sic 1，其后生动物类似物（Rb或p27）拮抗细胞周期进入。去除Whi 5和Stb 1可使far 1 α cln 2 β细胞部分逃离G1期阻滞，沿着G1/S基因的部分去阻遏，这意味着抑制G1/S转录的抑制剂非依赖性途径。这条途径可能涉及信息素诱导的Tec 1降解，Tec 1是细胞周期蛋白CLN 1的转录激活因子，因为Tec 1的稳定也会导致部分G1逃逸infar 1细胞周期蛋白CLN 2细胞，这与Whi 5/Stb 1去除是相加的。DeletingSIC 1单独强烈破坏Far 1-独立的G1期阻滞，揭示了B型细胞周期蛋白-Cdk活性的抑制可以增强弱阻滞途径。有趣的是，虽然far 1 pneumocln 2 pneumocln 1细胞逃脱G1逮捕，他们失去了活力，在信息素暴露，表明G1退出是有害的，如果逮捕信号仍然活跃。总的来说，我们的研究结果说明了多种不同的G1/S制动机制如何有助于防止过早的细胞周期承诺，并确保强大的信号诱导的G1期阻滞。
In budding yeast, mating pheromones arrest the cell cycle in G1 phase via a pheromone-activated Cdk-inhibitor (CKI) protein, Far1. Alternate pathways must also exist, however, because deleting the cyclinCLN2restores pheromone arrest tofar1∆cells. Here we probe whether these alternate pathways require the G1/S transcriptional repressors Whi5 and Stb1 or the CKI protein Sic1, whose metazoan analogues (Rb or p27) antagonize cell cycle entry. Removing Whi5 and Stb1 allows partial escape from G1 arrest infar1∆ cln2∆cells, along with partial derepression of G1/S genes, which implies a repressor-independent route for inhibiting G1/S transcription. This route likely involves pheromone-induced degradation of Tec1, a transcriptional activator of the cyclinCLN1, because Tec1 stabilization also causes partial G1 escape infar1∆ cln2∆cells, and this is additive with Whi5/Stb1 removal. DeletingSIC1alone strongly disrupts Far1-independent G1 arrest, revealing that inhibition of B-type cyclin-Cdk activity can empower weak arrest pathways. Of interest, althoughfar1∆ cln2∆ sic1∆cells escaped G1 arrest, they lost viability during pheromone exposure, indicating that G1 exit is deleterious if the arrest signal remains active. Overall our findings illustrate how multiple distinct G1/S-braking mechanisms help to prevent premature cell cycle commitment and ensure a robust signal-induced G1 arrest.