通过MYC介导的miRNA抑制来调节体轴
Anna P Petrashen1, Andrew D Verdesca1, Jill A Kreiling1
1Center on the Biology of Aging, Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, United States.
Frontiers in cell and developmental biology
|November 1, 2023
概括
在小鼠中减少MYC表达增加了寿命,并减少了与年龄有关的疾病. 这项研究揭示了MYC通过miRNAs调节IGF1信号,影响寿命,并可能减轻骨质疏松症.
科学领域:
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
- 衰老研究研究 衰老研究
背景情况:
- 转录因子MYC在人类癌症中经常过度表达,导致瘤的发展.
- 相反,Myc异合体小鼠中MYC表达的减少与寿命的延长和与年龄有关的疾病的减少有关.
- 异构细胞表现出减少的mTOR和IGF1信号传递,与寿命相关的途径.
研究的目的:
- 调查MYC,mTOR和IGF1信号之间的监管网络.
- 提供有关影响IGF1水平的反循环在Myc异卵性小鼠中的证据.
- 阐明微RNAs (miRNAs) 在介导MYC对IGF1.1的影响中的作用.
主要方法:
- 在Myc异合性小鼠中分析循环和肝脏IGF1水平.
- 阿尔戈诺特 (AGO) -CLIP测序用于识别Igf1转录中的miRNA结合位.
- 在初级肝细胞和体内对miR-122进行实验性操纵,以评估IGF1调节.
- 在垂体和骨中测量生长激素 (GH) 和IGF1水平.
主要成果:
- 在雌性Myc异构体中减少MYC表达,特别减少循环和肝脏IGF1蛋白.
- 通过AGO-CLIP测序,在雌性异构成的Igf1转录中的let-7,miR-122和miR-29目标位点发现了AGO结合的丰富.
- 在肝细胞和体内,miR-122的上调显著降低了IGF1蛋白 (但不是mRNA).
- 降低IGF1导致通过负反增加垂体GH产量,而骨IGF1保持不变.
结论:
- 减少MYC表达降低IGF1的调节,特别是在女性中,通过miRNA介导的Igf1转录的翻译抑制.
- 这个MYC-IGF1-miRNA轴代表一个反循环,影响衰老和与年龄相关的疾病.
- 这些发现表明,尽管全身IGF1.1水平较低,但女性Myc异构体骨质疏松症发病率降低的机制存在.
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