Parathyroid gland-specific deletion of the mouse Men1 gene results in parathyroid neoplasia and hypercalcemic hyperparathyroidism.
The inactivation of the MEN1 tumor suppressor gene in patients leads to a constellation of changes in endocrine tissues, including parathyroid neoplasia, pituitary adenomas, pancreatic neuroendocrine tumors, and carcinoids. To study the pathophysiological consequences of the deletion of the MEN1 gene, we set out to create a mouse model of hyperparathyroidism resulting from the deletion of the Men1 gene in parathyroid tissue. We introduced a Men1 gene flanked by loxP sites into the mouse germ line and then used a parathyroid cell-specific promoter to drive the expression of Cre recombinase, resulting in the deletion of the Men1 gene. Here, we show that loss of Men1 gene function in the parathyroid glands of mice results in histological changes consistent with parathyroid neoplasia as well as systemic hypercalcemia. This model provides a means for dissecting the molecular basis of this familial cancer syndrome and may allow for the development of new strategies to treat related forms of hypercalcemia.
Libutti
Steven K
SK
Surgery Branch, Center for Cancer Research, National Cancer Institute/NIH, 10 Center Drive, Room 2B07, Bethesda, MD 20892, USA. Steven_Libutti@nih.gov
Crabtree
Judy S
JS
Lorang
Dominique
D
Burns
A Lee
AL
Mazzanti
Chiara
C
Hewitt
Stephen M
SM
O'Connor
Sarah
S
Ward
Jerrold M
JM
Emmert-Buck
Michael R
MR
Remaley
Alan
A
Miller
Marshall
M
Turner
Ewa
E
Alexander
H Richard
HR
Arnold
Andrew
A
Marx
Stephen J
SJ
Collins
Francis S
FS
Spiegel
Allen M
AM
D000818:Animals; D002118:Calcium / Q000097:blood; D003433:Crosses, Genetic; D005260:Female; D017353:Gene Deletion; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000235:genetics*; D006961:Hyperparathyroidism / Q000097:blood / Q000235:genetics*; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010282:Parathyroid Neoplasms / Q000097:blood / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics
C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases; D002118:Calcium