Science Signaling JCR分区-刊鹿论文编译

The induction of HAD-like phosphatases by multiple signaling pathways confers resistance to the metabolic inhibitor 2-deoxyglucose

Abstract:

An evolutionarily conserved family of phosphatases enables cells to resist the toxic metabolic effects of 2-deoxyglucose. Resisting a metabolic poison Once imported into cells and phosphorylated, the glucose analog 2-deoxyglucose (2DG) inhibits glycolysis, leading to the proposal of using 2DG as a cancer treatment. Using yeast as a model, Defenouillère et al. investigated how cells become resistant to 2DG. Exposure to 2DG activated several signaling pathways that resulted in the increased expression of the gene encoding the phosphatase Dog2. In contrast, glucose availability transcriptionally repressed DOG2 expression. When overexpressed, a human homolog of Dog2 conferred 2DG resistance to human cells, suggesting that cancer cells with increased abundance of this phosphatase could escape the toxic effects of 2DG. Anti-cancer strategies that target the glycolytic metabolism of tumors have been proposed. The glucose analog 2-deoxyglucose (2DG) is imported into cells and, after phosphorylation, becomes 2DG-6-phosphate, a toxic by-product that inhibits glycolysis. Using yeast as a model, we performed an unbiased mass spectrometry–based approach to probe the cellular effects of 2DG on the proteome and study resistance mechanisms to 2DG. We found that two phosphatases that target 2DG-6-phosphate were induced upon exposure to 2DG and participated in 2DG detoxification. Dog1 and Dog2 are HAD (haloacid dehalogenase)–like phosphatases, which are evolutionarily conserved. 2DG induced Dog2 by activating several signaling pathways, such as the stress response pathway mediated by the p38 MAPK ortholog Hog1, the unfolded protein response (UPR) triggered by 2DG-induced ER stress, and the cell wall integrity (CWI) pathway mediated by the MAPK Slt2. Loss of the UPR or CWI pathways led to 2DG hypersensitivity. In contrast, mutants impaired in the glucose-mediated repression of genes were 2DG resistant because glucose availability transcriptionally repressed DOG2 by inhibiting signaling mediated by the AMPK ortholog Snf1. The characterization and genome resequencing of spontaneous 2DG-resistant mutants revealed that DOG2 overexpression was a common strategy underlying 2DG resistance. The human Dog2 homolog HDHD1 displayed phosphatase activity toward 2DG-6-phosphate in vitro and its overexpression conferred 2DG resistance in HeLa cells, suggesting that this 2DG phosphatase could interfere with 2DG-based chemotherapies. These results show that HAD-like phosphatases are evolutionarily conserved regulators of 2DG resistance.

Author Listing： Quentin Defenouillère;Agathe Verraes;Clotilde Laussel;Anne Friedrich;Joseph Schacherer;Sébastien Léon

Volume： 12

Pages： None

DOI： 10.1126/scisignal.aaw8000

Language： English

Journal： Science Signaling

Science Signaling

SCI SIGNAL

影响因子：6.6

是否综述期刊：是

是否OA：否

是否预警：不在预警名单内

发行时间：-

ISSN：1945-0877

发刊频率：-

收录数据库：SCIE/Scopus收录

出版国家/地区：UNITED STATES

出版社：American Association for the Advancement of Science

期刊介绍

Uncovering mechanisms in biology, gaining insights into physiology and diseaseScience Signaling is a weekly, online multidisciplinary journal for the life sciences. The aim of the journal editors is to publish studies that uncover the basic mechanisms that underlie biological processes across all organisms. Particular emphasis is placed on studies that provide new insights into physiology; delineate aberrant mechanisms that cause disease; identify new potential therapeutic targets and strategies; and characterize the effects of drugs in vitro and in vivo.

揭示生物学机制，深入了解生理学和疾病科学信号是一个每周，在线多学科的生命科学杂志。期刊编辑的目标是发表研究，揭示所有生物体的生物过程的基本机制。特别强调提供生理学新见解的研究;描述引起疾病的异常机制;确定新的潜在治疗靶点和策略;并表征药物在体外和体内的作用。

年发文量	88
国人发稿量	15
国人发文占比	16.67%
自引率	0.0%
平均录取率	-
平均审稿周期	-
版面费	-
偏重研究方向	BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY
期刊官网	http://stke.sciencemag.org/
投稿链接	https://cts.sciencemag.org/scc/login.html

质量指标占比

研究类文章占比	OA被引用占比	撤稿占比	出版后修正文章占比
94.32%	1.73%	0.00%	0.00%

预警情况

时间	预警情况
2025年03月发布的2025版	不在预警名单中
2024年02月发布的2024版	不在预警名单中
2023年01月发布的2023版	不在预警名单中
2021年12月发布的2021版	不在预警名单中
2020年12月发布的2020版	不在预警名单中

JCR分区 WOS分区等级：Q1区

版本	按学科	分区
WOS期刊SCI分区（2021-2022年最新版）

中科院分区

版本	大类学科	小类学科	Top期刊	综述期刊
	生物学 1区	CELL BIOLOGY 细胞生物学 2区 BIOCHEMISTRY & MOLECULAR BIOLOGY 生化与分子生物学 1区	否	是
2021年12月基础版	生物 2区	CELL BIOLOGY 细胞生物学 2区 BIOCHEMISTRY & MOLECULAR BIOLOGY 生化与分子生物学 2区	否	否
2021年12月升级版	生物学 1区	CELL BIOLOGY 细胞生物学 2区 BIOCHEMISTRY & MOLECULAR BIOLOGY 生化与分子生物学 1区	否	是
2020年12月旧的升级版	生物学 1区	CELL BIOLOGY 细胞生物学 2区 BIOCHEMISTRY & MOLECULAR BIOLOGY 生化与分子生物学 2区	否	是
2022年12月最新升级版	生物学 1区	CELL BIOLOGY 细胞生物学 2区 BIOCHEMISTRY & MOLECULAR BIOLOGY 生化与分子生物学 2区	否	是