Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta, T2N 4N1, Canada.
Arnie Charbonneau Cancer Institute, Departments of Biochemistry and Molecular Biology and Oncology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta, T2N 4N1, Canada.
Mech Ageing Dev. 2019 Jan;177:109-117. doi: 10.1016/j.mad.2018.06.004. Epub 2018 Jun 19.
Replicative capacity of normal human cells decreases as telomeric sequence is lost at each division. It is believed that when a subset of chromosomes reach a critically short length, an ATM-initiated and p53-mediated transcriptional response inhibits cell growth, promoting cell senescence. In addition to loss of telomeric sequence, senescence can be induced by other stresses including ionizing radiation, oxidative damage, chemical crosslinkers like the chemotherapeutic agent cisplatin, as well as overactivation of oncogenes and tumor suppressors. Our group found that the expression of an isoform of the INhibitor of Growth 1 gene called ING1a increases approximately 10-fold as fibroblasts approach senescence and that forced expression rapidly induces a senescent phenotype in primary diploid fibroblasts, epithelial and endothelial cells that resembles replicative senescence by most physical and biochemical measures. ING1a induces these changes through strongly inhibiting endocytosis to block mitogen signaling by inducing the expression of intersectin 2, a key scaffolding protein of the endosomal pathway. This, in turn increases the expression of Rb and of p57 and p16 that serve to maintain Rb is an active, growth inhibitory state. The ING1a model is currently being used to better understand the mechanism(s) responsible for activating Rb to enforce the senescent state.
正常人类细胞的复制能力会随着端粒序列在每次分裂中丢失而降低。人们认为，当一部分染色体达到临界短长度时，ATM 启动和 p53 介导的转录反应会抑制细胞生长，促进细胞衰老。除了端粒序列的丢失，衰老还可以由其他应激引起，包括电离辐射、氧化损伤、化学交联剂（如化疗药物顺铂）以及癌基因和肿瘤抑制基因的过度激活。我们的小组发现，称为 ING1a 的生长抑制剂 1 基因的一种异构体的表达在成纤维细胞接近衰老时增加约 10 倍，并且强制表达会迅速在原代二倍体成纤维细胞、上皮细胞和内皮细胞中诱导出类似于复制衰老的衰老表型，通过大多数物理和生化测量。ING1a 通过强烈抑制内吞作用来阻止有丝分裂原信号，从而诱导内体途径的关键支架蛋白 intersectin 2 的表达，从而诱导这些变化。这反过来又增加了 Rb 和 p57 和 p16 的表达，这些蛋白有助于维持 Rb 处于活跃的、抑制生长的状态。ING1a 模型目前正被用于更好地理解激活 Rb 以强制衰老状态的机制。
