Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity
Hypoxia-selective macroautophagy and cell survival signaled by autocrine PDGFR activity
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DOI：
10.1101/gad.521709
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发表时间：
2009-06-01
影响因子：
10.5
通讯作者：
Ryan, Kevin M.
中科院分区：
文献类型：
--
作者：
Wilkinson, Simon;O'Prey, Jim;Ryan, Kevin M.
巨细胞自噬的选择性调节仍然不清楚。在这里，我们报告说，PDGFR信号是一个重要的选择性启动子缺氧诱导的大自噬。肿瘤细胞中缺氧诱导的巨自噬也是HIF 1 α依赖性的，HIF 1 α整合了来自PDGFR和氧张力的信号。尽管通过HIF 1 α mRNA的代偿性增加缓冲了稳态蛋白水平，但PDGFR信号传导的抑制降低了HIF 1 α的半衰期。这显著改变了HIF 1 α蛋白库的动力学，从而减少了HIF 1 α转录组。由于自分泌生长因子信号传导是许多癌症的标志，HIF 1 α介导的巨自噬的细胞自主增强可能代表了在缺氧条件下增加肿瘤细胞存活的机制。
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 HIF1 alpha-dependent, with HIF1 alpha integrating signals from PDGFRs and oxygen tension. Inhibition of PDGFR signaling reduces HIF1 alpha half-life, despite buffering of steady-state protein levels by a compensatory increase in HIF1 alpha mRNA. This markedly changes HIF1 alpha protein pool dynamics, and consequently reduces the HIF1 alpha transcriptome. As autocrine growth factor signaling is a hallmark of many cancers, cell-autonomous enhancement of HIF1 alpha-mediated macroautophagy may represent a mechanism for augmenting tumor cell survival under hypoxic conditions.