Cobley David, Hálová Lenka, Schauries Marie, Kaczmarek Adrian, Franz-Wachtel Mirita, Du Wei, Krug Karsten, Maček Boris, Petersen Janni
Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom.
Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, SA, Australia.
PLoS One. 2017 Mar 8;12(3):e0172740. doi: 10.1371/journal.pone.0172740. eCollection 2017.
Tight coupling of cell growth and cell cycle progression enable cells to adjust their rate of division, and therefore size, to the demands of proliferation in varying nutritional environments. Nutrient stress promotes inhibition of Target Of Rapamycin Complex 1 (TORC1) activity. In fission yeast, reduced TORC1 activity advances mitotic onset and switches growth to a sustained proliferation at reduced cell size. A screen for mutants, that failed to advance mitosis upon nitrogen stress, identified a mutant in the PIKFYVE 1-phosphatidylinositol-3-phosphate 5-kinase fission yeast homolog Ste12. Ste12PIKFYVE deficient mutants were unable to advance the cell cycle to reduce cell size after a nitrogen downshift to poor nitrogen (proline) growth conditions. While it is well established that PI(3,5)P2 signalling is required for autophagy and that Ste12PIKFYVE mutants have enlarged vacuoles (yeast lysosomes), neither a block to autophagy or mutants that independently have enlarged vacuoles had any impact upon nitrogen control of mitotic commitment. The addition of rapamycin to Ste12PIKFYVE deficient mutants reduced cell size at division to suggest that Ste12PIKFYVE possibly functions upstream of TORC1. ste12 mutants display increased Torin1 (TOR inhibitor) sensitivity. However, no major impact on TORC1 or TORC2 activity was observed in the ste12 deficient mutants. In summary, Ste12PIKFYVE is required for nitrogen-stress mediated advancement of mitosis to reduce cell size at division.
细胞生长与细胞周期进程的紧密耦合使细胞能够根据不同营养环境下的增殖需求来调整其分裂速率，进而调整细胞大小。营养应激会促进对雷帕霉素复合物1（TORC1）活性的抑制。在裂殖酵母中，TORC1活性降低会使有丝分裂提前开始，并将生长转变为在较小细胞大小下的持续增殖。一项针对在氮胁迫下未能使有丝分裂提前的突变体的筛选，鉴定出了磷脂酰肌醇激酶FYVE 1 - 磷脂酰肌醇 - 3 - 磷酸5 - 激酶裂殖酵母同源物Ste12中的一个突变体。缺乏Ste12PIKFYVE的突变体在氮源转变为贫氮（脯氨酸）生长条件后，无法推进细胞周期以减小细胞大小。虽然PI(3,5)P2信号传导对于自噬是必需的，且Ste12PIKFYVE突变体具有增大的液泡（酵母溶酶体），但自噬阻断或独立具有增大液泡的突变体对有丝分裂承诺的氮控制均无任何影响。向缺乏Ste12PIKFYVE的突变体中添加雷帕霉素可降低分裂时的细胞大小，这表明Ste12PIKFYVE可能在TORC1的上游发挥作用。ste12突变体对Torin1（TOR抑制剂）的敏感性增加。然而，在缺乏ste12的突变体中未观察到对TORC1或TORC2活性的重大影响。总之，氮胁迫介导的有丝分裂提前以减小分裂时的细胞大小需要Ste12PIKFYVE。
