Differential expression of the regulated catecholamine secretory pathway in different hereditary forms of pheochromocytoma

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Graeme Eisenhofer - , Institut für Klinische Chemie und Laboratoriumsmedizin, Medizinische Klinik und Poliklinik 3 (Autor:in)
  • Thanh Truc Huynh - , Eunice Kennedy Shriver National Institute of Child Health and Human Development (Autor:in)
  • Abdel Elkahloun - , National Institutes of Health (NIH) (Autor:in)
  • John C. Morris - , National Cancer Institute (NCI) (Autor:in)
  • Gennady Bratslavsky - , National Cancer Institute (NCI) (Autor:in)
  • W. Marston Linehan - , National Cancer Institute (NCI) (Autor:in)
  • Zhengping Zhuang - , National Institutes of Health (NIH) (Autor:in)
  • Brian M. Balgley - , University of Maryland, College Park (Autor:in)
  • Cheng S. Lee - , University of Maryland, College Park (Autor:in)
  • Massimo Mannelli - , Università degli Studi di Firenze (Autor:in)
  • Jacques W.M. Lenders - , Radboud University Nijmegen (Autor:in)
  • Stefan R. Bornstein - , Medizinische Klinik und Poliklinik 3 (Autor:in)
  • Karel Pacak - , Eunice Kennedy Shriver National Institute of Child Health and Human Development (Autor:in)

Abstract

Pheochromocytomas in patients with von Hippel-Lindau (VHL) syndrome and multiple endocrine neoplasia type 2 (MEN 2) differ in the types and amounts of catecholamines produced and the resulting signs and symptoms. We hypothesized the presence of different processes of catecholamine release reflecting differential expression of components of the regulated secretory pathway among the two types of hereditary tumors. Differences in catecholamine secretion from tumors in patients with VHL syndrome (n = 47) and MEN 2 (n = 32) were examined using measurements of catecholamines in tumor tissue, urine, and plasma, the last of which was under baseline conditions in all subjects and in a subgroup of patients who received intravenous glucagon to provoke catecholamine release. Microarray and proteomics analyses, quantitative PCR, and Western blotting were used to assess expression of tumor tissue secretory pathway components. The rate constant for baseline catecholamine secretion was 20-fold higher in VHL than in MEN 2 tumors (0.359 ± 0.094 vs. 0.018 ± 0.009 day-1), but catecholamine release was responsive only to glucagon in MEN 2 tumors. Compared with tumors from MEN 2 patients, those from VHL patients were characterized by reduced expression of numerous components of the regulated secretory pathway (e.g., SNAP25, syntaxin, rabphilin 3A, annexin A7, calcium-dependent secretion activator). The mutation-dependent differences in expression of secretory pathway components indicate a more mature regulated secretory pathway in MEN 2 than VHL tumors. These data provide a unique mechanistic link to explain how variations in the molecular machinery governing exocytosis may contribute to clinical differences in the secretion of neurotransmitters or hormones and the subsequent presentation of a disease.

Details

OriginalspracheEnglisch
Seiten (von - bis)E1223-E1233
FachzeitschriftAmerican Journal of Physiology - Endocrinology and Metabolism
Jahrgang295
Ausgabenummer5
PublikationsstatusVeröffentlicht - Nov. 2008
Peer-Review-StatusJa

Externe IDs

PubMed 18854424

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Exocytosis, Multiple endocrine neoplasia type 2, Secretion, Von Hippel-Lindau