Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Dabral, Swati UNSPECIFIED UNSPECIFIED UNSPECIFIED Muecke, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Valasarajan, Chanil UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmoranzer, Mario UNSPECIFIED UNSPECIFIED UNSPECIFIED Wietelmann, Astrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Semenza, Gregg L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Meister, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Muley, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Seeger-Nukpezah, Tamina UNSPECIFIED orcid.org/0000-0002-4906-7834 UNSPECIFIED Samakovlis, Christos UNSPECIFIED orcid.org/0000-0002-9153-6040 UNSPECIFIED Weissmann, Norbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Grimminger, Frich UNSPECIFIED UNSPECIFIED UNSPECIFIED Seeger, Werner UNSPECIFIED orcid.org/0000-0003-1946-0894 UNSPECIFIED Savai, Rajkumar UNSPECIFIED UNSPECIFIED UNSPECIFIED Pullamsetti, Soni S. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language RASSF1A TUMOR-SUPPRESSOR; HYPOXIA-INDUCIBLE FACTORS; MOLECULAR-MECHANISMS; METHYLATION; GENE; LUNG; HIF-1; DEGRADATION; HIF-1-ALPHA; METABOLISM Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14830