WIP1是一种新的生长激素作用的特定点
Tugce Apaydin1, Svetlana Zonis1, Cuiqi Zhou1
1Department of Medicine, Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
iScience
|October 25, 2023
概括
增长激素 (GH) 通过诱导WIP1酸酶来抑制DNA损伤的修复,从而导致DNA损伤的积累. 抑制WIP1恢复了修复机制,提供了一个潜在的治疗点.
科学领域:
- 分子生物学分子生物学
- 蜂信号传输是如何进行的
- 癌症研究 癌症研究
背景情况:
- 修复DNA损伤 (DDR) 对于保持基因组稳定性至关重要.
- ATM 激酶,CHK2,p53 和 γH2AX 是 DDR 途径中的关键效应因子.
- 以前的研究表明,生长激素 (GH) 通过抑制pATM来抑制DDR,从而导致DNA损伤的积累.
研究的目的:
- 阐明GH抑制DNA损伤修复的机制.
- 为了确定参与GH介导的DDR抑制的特定分子点.
- 探索WIP1在GH信号传递中的作用及其对DNA损伤的影响.
主要方法:
- 研究了人类结肠细胞和肠道有机体中的GH受体 (GHR) 通过GH信号传递.
- 利用了与GH分泌瘤和GHK淘汰小鼠的老鼠异种移植模型.
- 分析了WIP1诱导,ATM酸化和DNA损伤标记物 (pATM, γH2AX).
- 阐明了Src,AMPK和HIPK2参与调节WIP1.1的信号通路.
- 评估了WIP1抑制对ATM酸化和DNA损伤的影响.
主要成果:
- GH通过GHR诱导野生类型的p53-诱导酸酶1 (WIP1),该酸酶使ATM及其效应物脱.
- 在GH分泌异源移植的小鼠和体腺瘤患者中诱导了WIP1,与抑制的pATM和γH2AX相关.
- 相反,在GHR淘汰赛小鼠中,结肠WIP1下降.
- 抑制WIP1恢复了ATM酸化,并逆转了GH诱导的DNA损伤.
- 确定了一种激活Src/AMPK的新型GH信号通路,导致HIPK2转移和抑制WIP1无处不在.
结论:
- GH通过诱导WIP1来促进DNA损伤的积累,WIP1是一种酸酶,可以禁用关键的DDR激酶.
- GH-GHR-WIP1轴代表了一种新的途径,有助于基因组不稳定.
- WIP1是GH介导的上皮细胞DNA损伤的特定分子标,表明其作为治疗标的潜力.
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