Expression and processing of parathyroid hormone-related protein in a pancreatic endocrine cell tumour associated with hypercalcaemia.
We describe a patient with a neuroendocrine tumour of the pancreas associated with hypercalcaemia which was attributed to production of parathyroid hormone-related protein (PTHrP) by the tumour. Plasma PTHrP 1-86 was significantly raised, and fell following surgical resection of the tumour. PTHrP mRNA and peptide were identified in tumour tissue by in-situ hybridization and immunohistochemistry respectively. PTHrP was quantitated in an extract of tumour tissue by three region-specific immunoassays (PTHrP 1-34 45.2 pmol/g, PTHrP 37-67 81.7 pmol/g, PTHrP 1-86 27.3 pmol/g) and suggested the presence of excess of amino-terminal and mid-region immunoreactivity. On chromatography of the tumour extract the first peak eluted as 22 kDa and comprised approximately equimolar 1-34, 37-67 and 1-86 activities. The second and major peak of 16 kDa contained only 37-67 activity, while the third peak of 6 kDa contained only 1-34 activity. This suggested that the tumour contained a native or intact form of PTHrP together with two major subfragments containing 37-67 and 1-34 activity respectively. Thus chromatographic separation and quantitation of PTHrP by region-specific immunoassays have provided new information on in-vivo proteolytic processing by tumour tissue by indicating that a site of cleavage is located between residues 17 and 61. Our findings are compatible with cleavage at residue 37, a site previously indicated from in-vitro studies.
Ratcliffe
W A
WA
Wolfson Research Laboratories, Queen Elizabeth Medical Centre, Birmingham, UK.
Bowden
S J
SJ
Dunne
F P
FP
Hughes
S
S
Emly
J F
JF
Baker
J T
JT
Pye
J K
JK
Williams
C P
CP
D000328:Adult; D002850:Chromatography, Gel; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000378:metabolism*; D007150:Immunohistochemistry; D018358:Neuroendocrine Tumors / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000032:analysis; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000032:analysis; D010455:Peptides / Q000032:analysis; D011506:Proteins / Q000032:analysis / Q000378:metabolism*; D019379:Teriparatide
C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D010455:Peptides; D011506:Proteins; C068871:parathyroid hormone-related protein (1-86); C087893:parathyroid hormone-related protein (37-67); D019379:Teriparatide; C066078:parathyroid hormone-related protein (1-141)