Menin inactivation leads to loss of transforming growth factor beta inhibition of parathyroid cell proliferation and parathyroid hormone secretion.
Primary hyperparathyroidism is a common endocrine disorder caused by parathyroid gland enlargement and excessive parathyroid hormone (PTH) secretion. However, the precise mechanisms of tumorigenesis of the parathyroids are unknown. Here we have investigated the roles of transforming growth factor (TGF)-beta and menin, the product of the multiple endocrine neoplasia type 1 (Men1) gene, in the proliferation and PTH production of parathyroid cells from either patients with secondary hyperparathyroidism or Men1. TGF-beta was expressed in the parathyroid endocrine cells. Addition of TGF-beta to parathyroid cells from patients with secondary hyperparathyroidism inhibited their proliferation and PTH secretion. These responses to TGF-beta were lost when menin was specifically inactivated by antisense oligonucleotides. Moreover, TGF-beta did not affect the proliferation and PTH production of parathyroid cells from a Men1 patient. These results indicate that menin is required for TGF-beta action in the parathyroid. We conclude that TGF-beta is an important autocrine/paracrine negative regulator of parathyroid cell proliferation and PTH secretion and that loss of TGF-beta signaling due to menin inactivation contributes to parathyroid tumorigenesis.
Sowa
Hideaki
H
Division of Endocrinology/Metabolism, Neurology and Hematology/Oncology, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-Cho, Chuo-ku, Kobe 650-0017, Japan.
Kaji
Hiroshi
H
Kitazawa
Riko
R
Kitazawa
Sohei
S
Tsukamoto
Tatsuo
T
Yano
Shozo
S
Tsukada
Toshihiko
T
Canaff
Lucie
L
Hendy
Geoffrey N
GN
Sugimoto
Toshitsugu
T
Chihara
Kazuo
K
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000378:metabolism* / Q000473:pathology; D018761:Multiple Endocrine Neoplasia Type 1 / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010280:Parathyroid Glands / Q000378:metabolism / Q000473:pathology*; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
C105373:MEN1 protein, human; D016376:Oligonucleotides, Antisense; D010281:Parathyroid Hormone; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta