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Li, M.* ; Richter, S.* ; Mohr, H. ; Drukewitz, S.* ; Poser, I.* ; Stanke, D.* ; Calsina, B.* ; Martinez-Montes, A.M.* ; Quinkler, M.* ; Timmers, H.J.L.M.* ; Nölting, S.* ; Beuschlein, F.* ; Remde, H.* ; Opocher, G.* ; Rapizzi, E.* ; Pacak, K.* ; Pamporaki, C.* ; Robledo, M.* ; Liu, L.* ; Jiang, J.* ; Bornstein, S.* ; Eisenhofer, G.* ; Fliedner, S.M.J.* ; Bechmann, N.*

Regulation of epinephrine biosynthesis in HRAS-mutant paragangliomas.

Endocr. Relat. Cancer 30:12 (2023)
Postprint DOI PMC
Open Access Green
The biochemical phenotype of paragangliomas (PGLs) is highly dependent on the underlying genetic background and tumor location. PGLs at extra-adrenal locations usually do not express phenylethanolamine N-methyltransferase (PNMT), the enzyme required for epinephrine production, which was explained by the absence of glucocorticoids. PGLs with pathogenic variants (PVs) in Harvey rat sarcoma viral oncogene homolog (HRAS) can occur in or outside of the adrenal, but always synthesize epinephrine independently of the localization. Here, we characterize the signaling pathways through which PVs in HRAS influence PNMT expression. Catecholamines, cortisol, and transcriptional features of PGL tissues with known genetic background were analyzed. Genetically modified rat pheochromocytoma cells carrying PVs in Hras were generated and analyzed for regulation of Pnmt expression. Elevated epinephrine contents in PGLs with PVs in HRAS were accompanied by enrichment in mitogen-activated protein kinase (MAPK) signaling compared to PGLs with PVs in genes that activate hypoxia pathways. In vitro, Hras PVs increased Pnmt expression and epinephrine biosynthesis through increased phosphorylation of stimulatory protein 1 via MAPK signaling. Here, we provide a molecular mechanism that explains the PV-dependent epinephrine production of PGLs.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mapk Pathway ; Catecholamines ; Glucocorticoids ; Paraganglioma ; Phenotype–genotype Correlations; Phenylethanolamine N-methyltransferase; H-ras; Pheochromocytoma; Hif2-alpha; Phenotypes; Mutations; Plasma; Gene
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 1351-0088
e-ISSN 1479-6821
Zeitschrift Endocrine-Related Cancer
Quellenangaben Band: 30, Heft: 12 Seiten: , Artikelnummer: 12 Supplement: ,
Verlag BioScientifica
Verlagsort Bristol
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502590-001
Förderungen
China Scholarship Council
National Natural Science Foundation of China
Paradifference Foundation
Accion Estrategica en Salud, cofinanciado a traves del Fondo Europeo de Desarrollo Regional (FEDER))
Umbrella of University Medicine Zurich
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
DOI 10.1530/ERC-23-0230
WOS ID 001108005000008
Scopus ID 85175404976
PubMed ID 37902037
Erfassungsdatum 2023-11-28
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