Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
Autophagy. 2012 Feb 1;8(2):278-80. doi: 10.4161/auto.8.2.18939.
Microtubule-associated protein 1 small form (MAP1S; originally named C19ORF5) was identified as serving as linkers to connect mitochondria with microtubules for trafficking, and to bridge the autophagy machinery with microtubules and mitochondria to affect autophagosomal biogenesis and degradation. We found that MAP1S levels become elevated immediately in response to diethylnitrosamine-induced or genome instability-driven metabolic stress in a murine model of hepatocarcinoma. Elevation of MAP1S enhances autophagy to remove p62-associated aggresomes and dysfunctional organelles that trigger DNA double-strand (DSB) breaks and genome instability. The early accumulation of an unstable genome prior to signs of tumorigenesis suggested that genome instability causes tumorigenesis. After tumorigenesis, tumor development then triggers the activation of autophagy to reduce genome instability in tumor foci. We concluded that an increase in MAP1S levels triggers autophagy in order to suppress genome instability so that both the incidence of diethylnitrosamine-induced hepatocarcinogenesis and malignant progression are suppressed. Thus, a link between MAP1S-enhanced autophagy and suppression of genomic instability and tumorigenesis has been established.
微管相关蛋白 1 小形式（MAP1S；最初命名为 C19ORF5）被鉴定为连接线粒体与微管的接头，用于运输，并连接自噬机制与微管和线粒体，以影响自噬体的生物发生和降解。我们发现，在肝癌小鼠模型中，MAP1S 水平会立即因二乙基亚硝胺诱导或基因组不稳定性驱动的代谢应激而升高。MAP1S 的升高增强了自噬作用，以去除 p62 相关的聚集物和功能失调的细胞器，这些细胞器会引发 DNA 双链（DSB）断裂和基因组不稳定性。在肿瘤发生之前，不稳定基因组的早期积累表明基因组不稳定性导致肿瘤发生。肿瘤发生后，肿瘤的发展继而触发自噬的激活，以减少肿瘤灶中的基因组不稳定性。我们得出结论，MAP1S 水平的增加引发自噬以抑制基因组不稳定性，从而抑制二乙基亚硝胺诱导的肝癌发生和恶性进展的发生率。因此，已经建立了 MAP1S 增强的自噬与抑制基因组不稳定性和肿瘤发生之间的联系。
