Menin inactivation leads to loss of transforming growth factor β inhibition of parathyroid cell proliferation and parathyroid hormone secretion

被引：45

作者：

Sowa, H

Kaji, H

Kitazawa, R

Kitazawa, S

Tsukamoto, T

Yano, S

Tsukada, T

Canaff, L

Hendy, GN

Sugimoto, T

Chihara, K

机构：

[1] Kobe Univ, Grad Sch Med, Div Endocrinol Metab Neurol & Hematol Oncol, Dept Clin Mol Med,Chuo Ku, Kobe, Hyogo 6500017, Japan

[2] Royal Victoria Hosp, Montreal, PQ H3A 1A1, Canada

[3] McGill Univ, Dept Med, Montreal, PQ, Canada

[4] McGill Univ, Dept Physiol, Montreal, PQ, Canada

[5] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[6] Natl Canc Ctr, Res Inst, Tumor Endocrinol Project, Tokyo 104, Japan

[7] Kobe Univ, Grad Sch Med, Dept Biomed Informat, Div Mol Pathol, Kobe, Hyogo, Japan

来源：

CANCER RESEARCH | 2004年 / 64卷 / 06期

关键词：

D O I：

10.1158/0008-5472.CAN-03-3334

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：2222 / 2228

页数：7

共 46 条

[1]

Arnold A, 2002, J BONE MINER RES, V17, pN30

[2] MONOCLONALITY OF PARATHYROID TUMORS IN CHRONIC-RENAL-FAILURE AND IN PRIMARY PARATHYROID HYPERPLASIA [J].

ARNOLD, A ;

BROWN, MF ;

URENA, P ;

GAZ, RD ;

SARFATI, E ;

DRUEKE, TB .

JOURNAL OF CLINICAL INVESTIGATION, 1995, 95 (05) :2047-2053

[3] Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1 [J].

Bertolino, P ;

Tong, WM ;

Galendo, D ;

Wang, ZQ ;

Zhang, CX .

MOLECULAR ENDOCRINOLOGY, 2003, 17 (09) :1880-1892

[4]

Böttinger EP, 1997, CANCER RES, V57, P5564

[5] Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism [J].

Carling, T ;

Correa, P ;

Hessman, O ;

Hedberg, J ;

Skogseid, B ;

Lindberg, D ;

Rastad, J ;

Westin, G ;

Åkerström, G .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1998, 83 (08) :2960-2963

[6] Positional cloning of the gene for multiple endocrine neoplasia-type 1 [J].

Chandrasekharappa, SC ;

Guru, SC ;

Manickam, P ;

Olufemi, SE ;

Collins, FS ;

EmmertBuck, MR ;

Debelenko, LV ;

Zhuang, ZP ;

Lubensky, IA ;

Liotta, LA ;

Crabtree, JS ;

Wang, YP ;

Roe, BA ;

Weisemann, J ;

Boguski, MS ;

Agarwal, SK ;

Kester, MB ;

Kim, YS ;

Heppner, C ;

Dong, QH ;

Spiegel, AM ;

Burns, AL ;

Marx, SJ .

SCIENCE, 1997, 276 (5311) :404-407

[7] p21WAF1 and TGF-α mediate parathyroid growth arrest by vitamin D and high calcium [J].

Cozzolino, M ;

Lu, Y ;

Finch, J ;

Slatopolsky, E ;

Dusso, AS .

KIDNEY INTERNATIONAL, 2001, 60 (06) :2109-2117

[8] A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors [J].

Crabtree, JS ;

Scacheri, PC ;

Ward, JM ;

Garrett-Beal, L ;

Emmert-Buck, MR ;

Edgemon, KA ;

Lorang, D ;

Libutti, SK ;

Chandrasekharappa, SC ;

Marx, SJ ;

Spiegel, AM ;

Collins, FS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (03) :1118-1123

[9] Role of transforming growth factor-β signaling in cancer [J].

de Caestecker, MP ;

Piek, E ;

Roberts, AB .

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2000, 92 (17) :1388-1402

[10] INHIBITION OF PROLACTIN GENE-TRANSCRIPTION BY TRANSFORMING GROWTH-FACTOR-BETA IN GH3 CELLS [J].

DELIDOW, BC ;

BILLIS, WM ;

AGARWAL, P ;

WHITE, BA .

MOLECULAR ENDOCRINOLOGY, 1991, 5 (11) :1716-1722

← 1 2 3 4 5 →