title: Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice.
abstract: Mitotic arrest-deficient protein 1 (MAD1) is a component of the mitotic spindle assembly checkpoint. We have created a knockout mouse model to examine the physiologic consequence of reduced MAD1 function. Mad1(+/-) mice were successfully generated, but repeated paired mating of Mad1(+/-) with Mad1(+/-) mice failed to produce a single Mad1(-/-) animal, suggesting that the latter genotype is embryonic lethal. In aging studies conducted for >18 months, Mad1(+/-) mice compared with control wild-type (wt) littermates showed a 2-fold higher incidence of constitutive tumors. Moreover, 42% of Mad1(+/-) (P < 0.03), but 0% of wt, mice developed neoplasia after treatment with vincristine, a microtubule depolymerization agent. Mad1(+/-) mouse embryonic fibroblasts (MEF) were found to be more prone than wt cells to become aneuploid; Mad1(+/-), but not wt, MEFs produced fibrosarcomas when explanted into nude mice. Our results indicate an essential MAD1 function in mouse development and correlate Mad1 haploinsufficiency with increased constitutive tumors.
authors.affiliation: Molecular Virology Section, Laboratory of Molecular Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Iwanaga
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chi
authors.forename: Akiko
authors.initials: A
authors.lastname: Miyazato
authors.forename: Sergey
authors.initials: S
authors.lastname: Sheleg
authors.forename: Kerstin
authors.initials: K
authors.lastname: Haller
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Peloponese
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
authors.forename: Kuan-Teh
authors.initials: KT
authors.lastname: Jeang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D042822:Genomic Instability; D006238:Haploidy; D064246:Mad2 Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; C501385:Mad1l1 protein, mouse; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; D009687:Nuclear Proteins; D014750:Vincristine