Department of Lung Development and Remodeling, Member of the German Center for Lung Research (DZL), Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.
MRI and µCT Service Group, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, 61231, Germany.
Nat Commun. 2019 May 13;10(1):2130. doi: 10.1038/s41467-019-10044-z.
Hypoxia signaling plays a major role in non-malignant and malignant hyperproliferative diseases. Pulmonary hypertension (PH), a hypoxia-driven vascular disease, is characterized by a glycolytic switch similar to the Warburg effect in cancer. Ras association domain family 1A (RASSF1A) is a scaffold protein that acts as a tumour suppressor. Here we show that hypoxia promotes stabilization of RASSF1A through NOX-1- and protein kinase C- dependent phosphorylation. In parallel, hypoxia inducible factor-1 α (HIF-1α) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1α, blocks its prolyl-hydroxylation and proteasomal degradation, and thus enhances the activation of the glycolytic switch. We find that this mechanism operates in experimental hypoxia-induced PH, which is blocked in RASSF1A knockout mice, in human primary PH vascular cells, and in a subset of human lung cancer cells. We conclude that RASSF1A-HIF-1α forms a feedforward loop driving hypoxia signaling in PH and cancer.
缺氧信号在非恶性和恶性增殖性疾病中起主要作用。肺动脉高压 (PH) 是一种缺氧驱动的血管疾病，其特征是糖酵解开关类似于癌症中的沃伯格效应。Ras 相关结构域家族 1A (RASSF1A) 是一种支架蛋白，具有肿瘤抑制作用。在这里，我们表明缺氧通过 NOX-1 和蛋白激酶 C 依赖性磷酸化促进 RASSF1A 的稳定。平行地，缺氧诱导因子-1α (HIF-1α) 通过 RASSF1A 启动子区域中的 HIF 结合位点激活 RASSF1A 转录。相反，RASSF1A 结合到 HIF-1α 上，阻止其脯氨酰羟化和蛋白酶体降解，从而增强糖酵解开关的激活。我们发现这种机制在实验性缺氧诱导的 PH 中起作用，在 RASSF1A 敲除小鼠、人原发性 PH 血管细胞和一部分人肺癌细胞中被阻断。我们得出结论，RASSF1A-HIF-1α 形成一个正反馈环，在 PH 和癌症中驱动缺氧信号。
