Dabral, Swati, Muecke, Christian, Valasarajan, Chanil, Schmoranzer, Mario, Wietelmann, Astrid, Semenza, Gregg L., Meister, Michael, Muley, Thomas, Seeger-Nukpezah, Tamina ORCID: 0000-0002-4906-7834, Samakovlis, Christos ORCID: 0000-0002-9153-6040, Weissmann, Norbert, Grimminger, Frich, Seeger, Werner ORCID: 0000-0003-1946-0894, Savai, Rajkumar and Pullamsetti, Soni S. (2019). A RASSF1A-HIF1 alpha loop drives Warburg effect in cancer and pulmonary hypertension. Nat. Commun., 10. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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Abstract

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 alpha (HIF-1 alpha) activates RASSF1A transcription via HIF-binding sites in the RASSF1A promoter region. Vice versa, RASSF1A binds to HIF-1 alpha, 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-1 alpha forms a feedforward loop driving hypoxia signaling in PH and cancer.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dabral, SwatiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muecke, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Valasarajan, ChanilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmoranzer, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wietelmann, AstridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Semenza, Gregg L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meister, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muley, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger-Nukpezah, TaminaUNSPECIFIEDorcid.org/0000-0002-4906-7834UNSPECIFIED
Samakovlis, ChristosUNSPECIFIEDorcid.org/0000-0002-9153-6040UNSPECIFIED
Weissmann, NorbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grimminger, FrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger, WernerUNSPECIFIEDorcid.org/0000-0003-1946-0894UNSPECIFIED
Savai, RajkumarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pullamsetti, Soni S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-148303
DOI: 10.1038/s41467-019-10044-z
Journal or Publication Title: Nat. Commun.
Volume: 10
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RASSF1A TUMOR-SUPPRESSOR; HYPOXIA-INDUCIBLE FACTORS; MOLECULAR-MECHANISMS; METHYLATION; GENE; LUNG; HIF-1; DEGRADATION; HIF-1-ALPHA; METABOLISMMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14830

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