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. 2019 May 13;10:2130. doi: 10.1038/s41467-019-10044-z

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 9 — Schematic depicture of RASFF1A mediated HIF regulation. Under normoxia, HIF1α is hydroxlyated at proline residues by PHDs, ubiquitinated, followed by proteasomal degradation. Under hypoxia, RASSF1A is phosphorylated by ROS activated PKCα, leading to increased stability. Increased RASSF1A binds to HIF1α, preventing its binding to PHD2 and prolyl hydroxylation, increased nuclear translocation and subsequent transcriptional activity. This in turn leads to increased expression of glycolytic genes (PDK1, HK2, LDHA) and RASSF1A itself, giving rise to a feed forward loop and increased proliferation and glycolysis, manifesting in pulmonary hypertension and lung cancer pathogenesis. RASSF1A: Ras association domain family 1A, pVHL: von Hippel-Lindau tumor suppressor protein, PHD2/3: prolyl hydroxylase 2/3, HIF1α: hypoxia-inducible factor 1 alpha, HIF1β: hypoxia-inducible factor 1 beta, HRE: hypoxia-response elements, Ub: ubiquitin, OH: hydroxylation, Pro: proline, NADPH: nicotinamide adenine dinucleotide phosphate hydrogen, ROS: reactive oxygen species, NOX1: NADPH oxidase 1, NADP: nicotinamide adenine dinucleotide phosphate, PKCα: protein kinase C alpha, P: phosphorylation, HK2: hexokinase 2, PDK1: pyruvate dehydrogenase kinase, isozyme 1, LDHA: lactate dehydrogenase A