Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1

被引:49
作者
Busygina, V
Suphapeetiporn, K
Marek, LR
Stowers, RS
Xu, TA
Bale, AE
机构
[1] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA
[2] Stanford Sch Med, Beckman Ctr, Dept Cellular & Mol Physiol, Stanford, CA 94305 USA
关键词
D O I
10.1093/hmg/ddh271
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant cancer predisposition syndrome, the gene for which encodes a nuclear protein, menin. The biochemical function of this protein has not been completely elucidated, but several studies have shown a role in transcriptional modulation through recruitment of histone deacetylase. The mechanism by which MEN1 mutations cause tumorigenesis is unknown. The Drosophila homolog of MEN1, Mnn1, encodes a protein 50% identical to human menin. In order to further elucidate the function of MEN1, we generated a null allele of this gene in Drosophila and showed that homozygous inactivation results in morphologically normal flies that are hypersensitive to ionizing radiation and two DNA cross-linking agents, nitrogen mustard and cisplatinum. The spectrum of agents to which mutant flies are sensitive and analysis of the molecular mechanisms of this sensitivity suggest a defect in nucleotide excision repair. Drosophila Mnn1 mutants have an elevated rate of both sporadic and DNA damage-induced mutations. In a genetic background heterozygous for lats, a Drosophila and vertebrate tumor suppressor gene, homozygous inactivation of Mnn1 enhanced somatic mutation of the second allele of lats and formation of multiple primary tumors. Our data indicate that Mnn1 is a novel member of the class of autosomal dominant cancer genes that function in maintenance of genomic integrity, similar to the BRCA and HNPCC genes.
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页码:2399 / 2408
页数:10
相关论文
共 69 条
[1]   Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription [J].
Agarwal, SK ;
Guru, SC ;
Heppner, C ;
Erdos, MR ;
Collins, RM ;
Park, SY ;
Saggar, S ;
Chandrasekharappa, SC ;
Collins, FS ;
Spiegel, AM ;
Marx, SJ ;
Burns, AL .
CELL, 1999, 96 (01) :143-152
[2]   Genetic ablation of the tumor suppresor menin causes lethality at mid-gestation with defects in multiple organs [J].
Bertolino, P ;
Radovanovic, I ;
Casse, H ;
Aguzzi, A ;
Wang, ZQ ;
Zhang, CX .
MECHANISMS OF DEVELOPMENT, 2003, 120 (05) :549-560
[3]   Conditional inactivation of the Men1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues [J].
Biondi, CA ;
Gartside, MG ;
Waring, P ;
Loffler, KA ;
Stark, MS ;
Magnuson, MA ;
Kay, GF ;
Hayward, NK .
MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (08) :3125-3131
[4]  
BOYD JB, 1990, GENETICS, V125, P813
[5]  
Brodsky MH, 2000, GENE DEV, V14, P666
[6]  
CannonAlbright LA, 1996, SEMIN ONCOL, V23, P1
[7]   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
[8]   Of mice and MEN1: Insulinomas in a conditional mouse knockout [J].
Crabtree, JS ;
Scacheri, PC ;
Ward, JM ;
McNally, SR ;
Swain, GP ;
Montagna, C ;
Hager, JH ;
Hanahan, D ;
Edlund, H ;
Magnuson, MA ;
Garrett-Beal, L ;
Burns, AL ;
Ried, T ;
Chandrasekharappa, SC ;
Marx, SJ ;
Spiegel, AM ;
Collins, FS .
MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (17) :6075-6085
[9]   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
[10]   Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung [J].
Debelenko, LV ;
Brambilla, E ;
Agarwal, SK ;
Swalwell, JI ;
Kester, MB ;
Lubensky, IA ;
Zhuang, ZP ;
Guru, SC ;
Manickam, P ;
Olufemi, SE ;
Chandrasekharappa, SC ;
Crabtree, JS ;
Kim, YS ;
Heppner, C ;
Burns, AL ;
Spiegel, AM ;
Marx, SJ ;
Liotta, LA ;
Collins, FS ;
Travis, WD ;
EmmertBuck, MR .
HUMAN MOLECULAR GENETICS, 1997, 6 (13) :2285-2290