GSK3β酸化Six1转录因子并调节其APC/CCdh1介导的蛋白质体降解
Asma Rafiq1, Sabreena Aashaq2, Iqra Jan1
1Department of Nanotechnology, School of Biological Sciences, University of Kashmir-, Srinagar 190006, India.
Cellular signalling
|January 1, 2024
概括
糖原合成酶激酶3β (GSK3β) 酸化Six1蛋白,调节其稳定性和降解. 这种相互作用会影响癌细胞的增殖和生存,这表明GSK3β.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 细胞生物学 细胞生物学
背景情况:
- 鼻眼同源1 (Six1) 是发育中的一个关键的转录因子,通过过度表达与癌症进展有关.
- 六一蛋白循环由阿纳促进复合体/循环体 (APC/C) 调节,但涉及的激酶仍未确定.
- 了解Six1调控对于向癌症扩散和转移至关重要.
研究的目的:
- 确定调节Six1蛋白解的激酶,并阐明癌症中Six1过度生产背后的机制.
- 研究GSK3β在Six1蛋白稳定性和降解中的作用.
- 探索细胞周期和癌症中GSK3β和Six1水平之间的关系.
主要方法:
- 生物化学试验证实Six1是GSK3β基质,包括相互作用和酸化部位映射 (Ser221).
- 药理抑制,siRNA淘汰和GSK3β过度表达,以评估其对Six1稳定性的影响.
- 脉冲追踪分析使用野生类型,仿 (Six1S221E) 和缺 (Six1S221A) 的Six1突变物来确定降解率.
- 在不同的GSK3β活性下,评估Six1与APC/C联合激活剂Cdh1的结合.
主要成果:
- GSK3β直接与Six1相互作用,并在Ser221中酸化Six1,这是碳氧末端的保存位点.
- 对于Six1蛋白降解来说,GSK3β活性是必不可少的;抑制或淘汰会增加Six1的稳定性.
- 与Six1S221A和野生型Six1相比,Six1S221E突变的半衰期显著更长,这表明酸化在降解中的作用.
- 通过调节其与Cdh1的相互作用,GSK3β防止Six1经历APC/C介导的蛋白解.
- 在整个细胞周期和各种癌症中观察到GSK3β和Six1蛋白水平之间的正相关性.
结论:
- GSK3β通过在Ser221上酸化它,从而促进其降解,作为Six1蛋白稳定性的关键调节者.
- 通过GSK3β介导的Six1酸化阻止了其被APC/C复合体识别,从而控制了其营业额.
- 激活GSK3β可能会导致某些人类癌症中Six1的过度产生,将GSK3β与癌症进展联系起来.
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