Thornton Gemma, Wilkinson Caroline R M, Toone W Mark, Jones Nic
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK.
Genes Cells. 2005 Oct;10(10):941-51. doi: 10.1111/j.1365-2443.2005.00891.x.
In this study, we show that a mutation isolated during a screen for determinants of chemosensitivity in S. pombe results in loss of function of a previously uncharacterized protein kinase now named Hal4. Hal4 shares sequence homology to Hal4 and Hal5 in S. cerevisiae, and previous evidence indicates that these kinases positively regulate the major potassium transporter Trk1,2 and thereby maintain the plasma membrane potential. Disruption of this ion homeostasis pathway results in a hyperpolarized membrane and a concomitant increased sensitivity to cations. We demonstrate that a mutation in hal4+ results in hyperpolarization of the plasma membrane. In addition to the original selection agent, the hal4-1 mutant is sensitive to a variety of chemotherapeutic agents and stress-inducing compounds. Furthermore, this wider chemosensitive phenotype is also displayed by corresponding mutants in S. cerevisiae, and in a trk1deltatrk2delta double deletion mutant in S. pombe. We propose that this pathway and its role in regulating the plasma membrane potential may act as a pleiotropic determinant of sensitivity to chemotherapeutic agents.
在本研究中，我们发现，在粟酒裂殖酵母化学敏感性决定因素筛选过程中分离出的一个突变导致一种先前未被鉴定的蛋白激酶（现命名为Hal4）功能丧失。Hal4与酿酒酵母中的Hal4和Hal5具有序列同源性，先前的证据表明，这些激酶正向调节主要的钾转运蛋白Trk1、2，从而维持质膜电位。这种离子稳态途径的破坏导致膜超极化，并伴随对阳离子敏感性增加。我们证明，hal4⁺中的一个突变导致质膜超极化。除了原始选择剂外，hal4-1突变体对多种化疗药物和应激诱导化合物敏感。此外，酿酒酵母中的相应突变体以及粟酒裂殖酵母中的trk1Δtrk2Δ双缺失突变体也表现出这种更广泛的化学敏感表型。我们认为，该途径及其在调节质膜电位中的作用可能是对化疗药物敏感性的多效性决定因素。
