自分泌血小板衍生生长因子受体（PDGFR）活性介导的缺氧选择性巨自噬与细胞存活信号。
Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity.
作者信息
Wilkinson Simon, O'Prey Jim, Fricker Michael, Ryan Kevin M
机构信息
Tumour Cell Death Laboratory, Beatson Institute for Cancer Research, Glasgow, United Kingdom.
出版信息
Genes Dev. 2009 Jun 1;23(11):1283-8. doi: 10.1101/gad.521709.
Abstract
The selective regulation of macroautophagy remains poorly defined. Here we report that PDGFR signaling is an essential selective promoter of hypoxia-induced macroautophagy. Hypoxia-induced macroautophagy in tumor cells is also HIF1alpha-dependent, with HIF1alpha integrating signals from PDGFRs and oxygen tension. Inhibition of PDGFR signaling reduces HIF1alpha half-life, despite buffering of steady-state protein levels by a compensatory increase in HIF1alpha mRNA. This markedly changes HIF1alpha protein pool dynamics, and consequently reduces the HIF1alpha transcriptome. As autocrine growth factor signaling is a hallmark of many cancers, cell-autonomous enhancement of HIF1alpha-mediated macroautophagy may represent a mechanism for augmenting tumor cell survival under hypoxic conditions.
摘要
巨自噬的选择性调控仍未得到很好的界定。在此我们报告，血小板衍生生长因子受体（PDGFR）信号传导是缺氧诱导的巨自噬的一种重要的选择性促进因子。肿瘤细胞中缺氧诱导的巨自噬也是缺氧诱导因子1α（HIF1α）依赖性的，其中HIF1α整合来自PDGFRs和氧张力的信号。尽管通过HIF1α mRNA的代偿性增加缓冲了稳态蛋白水平，但抑制PDGFR信号传导会降低HIF1α的半衰期。这显著改变了HIF1α蛋白池动态，从而减少了HIF1α转录组。由于自分泌生长因子信号传导是许多癌症的一个标志，HIF1α介导的巨自噬的细胞自主增强可能代表了一种在缺氧条件下增强肿瘤细胞存活的机制。
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