一个整合素α3β1-CSTF3信号轴调节Mmp9mRNA的替代多基解
Giesse Albeche Duarte1, Ramon Bossardi Ramos1, Lei Wu2
1Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA.
概括
皮肤细胞中的integrain α3β1信号通过调节替代多基化 (APA) 来控制mRNA长度. 这一途径影响伤口愈合和皮肤瘤的发展,提供新的治疗点.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 皮肤病学 皮肤病学
背景情况:
- 集成蛋白α3β1对于表皮角质细胞功能和皮肤重塑至关重要.
- 集成蛋白信号传递影响皮肤修复和瘤发生期间的基因表达和细胞过程.
研究的目的:
- 在体内研究整合素α3β1在调节Mmp9mRNA的替代多基解 (APA) 中的作用.
- 阐明将α3β1信号与APA联系起来的分子机制及其对角质细胞基因表达的影响.
主要方法:
- 使用可诱导的表皮特异性α3缺失的小鼠.
- 采用RNA in situ杂交来分析Mmp9转录变异在伤口愈合和表皮瘤中.
- 研究了α3β1-MEK/ERK信号对CSTF3表达和APA的影响.
- 使用DaPars2.2进行全基因组APA分析.
主要成果:
- α3β1的损失增加了在愈合的伤口和表皮瘤中长Mmp9转录的丰富性.
- α3β1-MEK/ERK信号传导诱导了CSTF3表达,这是APA的调节者.
- 对于Mmp9.9的CSTF3淘汰促进远端多基化位点 (PAS) 的使用.
- α3删除减少了Cstf3的表达,并改变了全基因组的APA.
- 识别了许多α3β1依赖的APA事件,包括在状细胞密室的基因中.
结论:
- 一个涉及α3β1-MEK/ERK-CSTF3的新型信号轴通过APA在角质细胞中调节转录后基因表达.
- 集成蛋白α3β1控制Mmp9mRNA处理,影响皮肤重塑,伤口愈合和表皮瘤发生.
- α3β1代表了皮肤伤口愈合和癌症治疗的潜在治疗标.
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