Hepatocyte DNA replication in growing liver requires either glutathione or a single allele of txnrd1.
Hepatocyte DNA replication in growing liver requires either glutathione or a single allele of txnrd1.
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DOI：
10.1016/j.freeradbiomed.2011.11.025
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发表时间：
2012-02-15
影响因子：
7.4
通讯作者：
Schmidt, Edward E.
中科院分区：
文献类型：
--
作者：
Prigge, Justin R.;Eriksson, Soil;Iverson, Sonya V.;Meade, Tesia A.;Capecchi, Mario R.;Arner, Elias S. J.;Schmidt, Edward E.
核糖核苷酸还原酶（RNR）的活性需要一个电子供体，在细菌、酵母和植物中，电子供体通常是还原性硫氧还蛋白（Trx）或还原性戊氧还蛋白（Grx）。缺乏谷胱甘肽还原酶的小鼠是存活的，尽管缺乏硫氧还蛋白还原酶1 （TrxR1）的小鼠是胚胎致死的，但一些研究表明，缺乏编码TrxR1的txnrd1基因的小鼠细胞可以正常增殖。为了更好地了解哺乳动物RNR的体内电子供体需求，我们在这里研究了trxr1缺陷肝细胞在小鼠肝脏中的复制是否采用trx还原活性的替代来源，还是仅依赖谷胱甘肽（GSH）途径。正常肝脏和遗传性TrxR1缺陷肝脏都没有表达大量编码TrxR2胞浆变异体的mRNA剪接形式，并且TrxR1缺陷肝脏显示出严重降低的总TrxR活性，使得任何替代TrxR酶活性都不太可能补充遗传性TrxR1缺陷。为了测试GSH通路是否为复制所必需，我们通过给幼鼠注射丁硫氨酸亚砜胺（BSO）来降低GSH水平。在未接受BSO的对照组中，有两个、一个或没有txnrd1功能等位基因的肝细胞的复制指数相似。在BSO治疗后，含有两个或一个该基因拷贝的肝细胞也正常。然而，完全缺乏功能性txnrd1基因的肝细胞在GSH耗尽后表现出严重降低的复制指数。我们得出结论，肝细胞在体内的增殖需要GSH或至少一个txnrd1的功能等位基因，这表明在肝脏生长过程中，GSH或trxr1依赖的氧化还原途径都可以独立地支持肝细胞增殖。
Ribonucleotide reductase (RNR) activity requires an electron donor, which in bacteria, yeast, and plants is usually either reduced thioredoxin (Trx) or reduced glutaredoxin (Grx). Mice lacking glutathione reductase are viable and, although mice lacking thioredoxin reductase 1 (TrxR1) are embryonic-lethal, several studies have shown that mouse cells lacking the txnrd1 gene, encoding TrxR1, can proliferate normally. To better understand the in vivo electron donor requirements for mammalian RNR, we here investigated whether replication of TrxR1-deficient hepatocytes in mouse livers employed either an alternative source of Trx-reducing activity or, instead, solely relied upon the glutathione (GSH) pathway. Neither normal nor genetically TrxR1-deficient livers expressed substantial levels of mRNA splice-forms encoding cytosolic variants of TrxR2, and the TrxR1-deficient livers showed severely diminished total TrxR activity, making it unlikely that any alternative TrxR enzyme activities complemented the genetic TrxR1 deficiency. To test whether the GSH pathway was required for replication, GSH levels were depleted by administration of buthionine sulfoximine (BSO) to juvenile mice. In controls not receiving BSO, replicative indexes were similar in hepatocytes having either two, one, or no functional alleles of txnrd1. Following BSO treatment, hepatocytes containing either two or one copies of this gene were also normal. However, hepatocytes completely lacking a functional txnrd1 gene exhibited severely reduced replicative indexes after GSH depletion. We conclude that hepatocyte proliferation in vivo requires either GSH or at least one functional allele of txnrd1, demonstrating that either the GSH- or TrxR1-dependent redox pathway can independently support hepatocyte proliferation during liver growth.
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