Differential expression of the regulated catecholamine secretory pathway in different hereditary forms of pheochromocytoma.
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.
Institute of Clinical Chemistry and Laboratory Medicine, University of Dresden, Dresden, Germany. Graeme.Eisenhofer@uniklinikum-dresden.de
Graeme
G
Eisenhofer
Thanh-Truc
TT
Huynh
Abdel
A
Elkahloun
John C
JC
Morris
Gennady
G
Bratslavsky
W Marston
WM
Linehan
Zhengping
Z
Zhuang
Brian M
BM
Balgley
Cheng S
CS
Lee
Massimo
M
Mannelli
Jacques W M
JW
Lenders
Stefan R
SR
Bornstein
Karel
K
Pacak
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D017310:Annexin A7 / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002395:Catecholamines / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002648:Child; D004837:Epinephrine / Q000097:blood; D005260:Female; D020869:Gene Expression Profiling; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood; D020411:Oligonucleotide Array Sequence Analysis; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D055571:Secretory Pathway / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism; D050827:Syntaxin 1 / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D017310:Annexin A7; C409027:CADPS protein, human; D002135:Calcium-Binding Proteins; D002395:Catecholamines; C120704:RPH3AL protein, human; C494208:SNAP25 protein, human; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1; D033921:Vesicular Transport Proteins; D005934:Glucagon; D020691:rab GTP-Binding Proteins; D009638:Norepinephrine; D004837:Epinephrine