致癌基因诱导的衰老
中文名称
通路描述
由高水平的 RAS/RAF/MAPK 信号通路激活所触发，例如由 RAS 或 RAF 蛋白的致癌突变引起，或由 EGFR 等生长因子受体的致癌突变引起，这些突变位于 RAS/RAF/MAPK 级联的上游。此外，E2F1、E2F2 或 E2F3 的高转录活性也可触发该过程，这通常是由于 RB1 肿瘤抑制基因的失功能所致。致癌信号会转录 CDKN2A 位点的肿瘤抑制基因 p16INK4A 和 p14ARF。p16INK4A 和 p14ARF 共享外显子 2 和 3，但由不同的启动子转录，使用不同的阅读框。虽然它们的 mRNA 同源且均受 miR-24 微 RNA 翻译抑制，但在氨基酸序列上无相似性，且执行不同的细胞功能。p16INK4A 作为 CDK4 和 CDK6 的抑制剂，磷酸化并抑制 RB1 蛋白，从而促进 G1 到 S 期的过渡和细胞周期进展。p14ARF 与 MDM2 泛素连接酶结合并使其不稳定，负责 TP53 的泛素化和降解。因此，p14ARF 水平的增加会导致 TP53 水平升高，并增加 TP53 靶基因（如 p21）的表达，触发 p53 介导的细胞周期停滞，并可能根据其他因素导致 p53 介导的凋亡。CDKN2B 位点编码 p15INK4B，它是 CDK4 和 CDK6 的抑制剂，位于 CDKN2A 位点附近，在 9p21 染色体带。p15INK4B 与 p16INK4A 共同促进人 T 淋巴细胞和鼠成纤维细胞的衰老。SMAD3 由 TGF-β1 信号激活，通过调节 MYC 和 p15INK4B 基因表达来控制小鼠多阶段癌变模型中的衰老。TGF-β诱导的 p15INK4B 表达对于肝细胞癌细胞系的衰老也很重要。MAP 激酶 MAPK1 (ERK2) 和 MAPK3 (ERK1) 由 RAS 信号激活，磷酸化核内的 ETS1 和 ETS2 转录因子。磷酸化的 ETS1 和 ETS2 能够结合 CDKN2A 位点的 RAS 反应元件 (RREs) 并刺激 p16INK4A 的转录。同时，激活的 ERK 磷酸化 ERF，该转录因子抑制 ETS2 的转录，导致 ERF 转位至细胞质并增加 ETS2 的转录。ETS2 可与 ID1 结合并被捕获，从而抑制 p16INK4A 的转录。p14ARF 的转录由 E2F 转录因子 (E2F1、E2F2 或 E2F3) 与 SP1 复合物结合到 p14ARF 启动子引起。致癌 RAS 信号通过未知机制影响线粒体代谢，导致活性氧 (ROS) 生成增加，从而触发氧化应激诱导的衰老途径。此外，致癌信号导致的细胞分裂速率增加会导致端粒缩短，这是另一个衰老触发因素。虽然 OIS 在培养细胞中已得到详细研究，但由于缺乏特异性生物标志物及其与其他衰老途径的相互联系，体内 OIS 的作用建立仍然困难。
英文描述
Downstream signaling of activated FGFR1 Signaling via FGFRs is mediated via direct recruitment of signaling proteins that bind to tyrosine auto-phosphorylation sites on the activated receptor and via closely linked docking proteins that become tyrosine phosphorylated in response to FGF-stimulation and form a complex with additional complement of signaling proteins.
The activation loop in the catalytic domain of FGFR maintains the PTK domain in an inactive or low activity state. The activation-loop of FGFR1, for instance, contains two tyrosine residues that must be autophosphorylated for maintaining the catalytic domain in an active state. In the autoinhibited configuration, a kinase invariant proline residue at the C-terminal end of the activation loop interferes with substrate binding while allowing access to ATP in the nucleotide binding site.
In addition to the catalytic PTK core, the cytoplasmic domain of FGFR contains several regulatory sequences. The juxtamembrane domain of FGFRs is considerably longer than that of other receptor tyrosine kinases. This region contains a highly conserved sequence that serves as a binding site for the phosphotyrosine binding (PTB) domain of FRS2. A variety of signaling proteins are phosphorylated in response to FGF stimulation, including Shc, phospholipase-C gamma and FRS2 leading to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape.
The activation loop in the catalytic domain of FGFR maintains the PTK domain in an inactive or low activity state. The activation-loop of FGFR1, for instance, contains two tyrosine residues that must be autophosphorylated for maintaining the catalytic domain in an active state. In the autoinhibited configuration, a kinase invariant proline residue at the C-terminal end of the activation loop interferes with substrate binding while allowing access to ATP in the nucleotide binding site.
In addition to the catalytic PTK core, the cytoplasmic domain of FGFR contains several regulatory sequences. The juxtamembrane domain of FGFRs is considerably longer than that of other receptor tyrosine kinases. This region contains a highly conserved sequence that serves as a binding site for the phosphotyrosine binding (PTB) domain of FRS2. A variety of signaling proteins are phosphorylated in response to FGF stimulation, including Shc, phospholipase-C gamma and FRS2 leading to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape.
所含基因
14 个基因