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Title: Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice

Abstract

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition, with cellular features similar to that of ataxia telangiectasia (AT). NBS results from mutations in the mammalian gene Nbs1 that codes for a 95-kDa protein called nibrin, NBS1, or p95. To establish an animal model for NBS, we attempted to generate NBS1 knockout mice. However, NBS1 gene knockouts were lethal at an early embryonic stage. NBS1 homozygous(-/-) blastocyst cells cultured in vitro showed retarded growth and subsequently underwent growth arrest within 5 days of culture. Apoptosis, assayed by TUNEL staining, was observed in NBSI homozygous(-/-) blastocyst cells cultured for four days. NBSI heterozygous(+/-) mice were normal, and exhibited no specific phenotype for at least one year. However, fibroblast cells from NBSI heterozygous(+/-) mice displayed an enhanced frequency of spontaneous transformation to anchorage-independent growth as compared to NBS1 wild-type(+/+) cells. Furthermore, heterozygous(+/-) mice exhibited a high incidence of hepatocellular carcinoma after one year compared to wild-type mice, even though no significant differences in the incidence of other tumors such as lung adenocarcinoma and lymphoma were observed. Taken together, these results strongly suggest that NBS1 heterozygosity and reduced NBSI expression inducesmore » formation of specific tumors in mice.« less

Authors:
; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
Life Sciences Division
OSTI Identifier:
943450
Report Number(s):
LBNL-50210
TRN: US200902%%270
DOE Contract Number:  
DE-AC02-05CH11231
Resource Type:
Technical Report
Country of Publication:
United States
Language:
English
Subject:
59; ANIMALS; APOPTOSIS; CARCINOMAS; CHROMOSOMES; FIBROBLASTS; GENES; IN VITRO; INSTABILITY; LUNGS; LYMPHOMAS; MALFORMATIONS; MICE; MUTATIONS; NEOPLASMS; PHENOTYPE; PROTEINS; TRANSFORMATIONS

Citation Formats

Kurimasa, Akihiro, Burma, Sandeep, Henrie, Melinda, Ouyang, Honghai, Osaki, Mitsuhiko, Ito, Hisao, Nagasawa, Hatsumi, Little, John B., Oshimura, Mitsuo, Li, Gloria C., and Chen, David J.. Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice. United States: N. p., 2002. Web. doi:10.2172/943450.
Kurimasa, Akihiro, Burma, Sandeep, Henrie, Melinda, Ouyang, Honghai, Osaki, Mitsuhiko, Ito, Hisao, Nagasawa, Hatsumi, Little, John B., Oshimura, Mitsuo, Li, Gloria C., & Chen, David J.. Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice. United States. doi:10.2172/943450.
Kurimasa, Akihiro, Burma, Sandeep, Henrie, Melinda, Ouyang, Honghai, Osaki, Mitsuhiko, Ito, Hisao, Nagasawa, Hatsumi, Little, John B., Oshimura, Mitsuo, Li, Gloria C., and Chen, David J.. Mon . "Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice". United States. doi:10.2172/943450. https://www.osti.gov/servlets/purl/943450.
@article{osti_943450,
title = {Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice},
author = {Kurimasa, Akihiro and Burma, Sandeep and Henrie, Melinda and Ouyang, Honghai and Osaki, Mitsuhiko and Ito, Hisao and Nagasawa, Hatsumi and Little, John B. and Oshimura, Mitsuo and Li, Gloria C. and Chen, David J.},
abstractNote = {Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition, with cellular features similar to that of ataxia telangiectasia (AT). NBS results from mutations in the mammalian gene Nbs1 that codes for a 95-kDa protein called nibrin, NBS1, or p95. To establish an animal model for NBS, we attempted to generate NBS1 knockout mice. However, NBS1 gene knockouts were lethal at an early embryonic stage. NBS1 homozygous(-/-) blastocyst cells cultured in vitro showed retarded growth and subsequently underwent growth arrest within 5 days of culture. Apoptosis, assayed by TUNEL staining, was observed in NBSI homozygous(-/-) blastocyst cells cultured for four days. NBSI heterozygous(+/-) mice were normal, and exhibited no specific phenotype for at least one year. However, fibroblast cells from NBSI heterozygous(+/-) mice displayed an enhanced frequency of spontaneous transformation to anchorage-independent growth as compared to NBS1 wild-type(+/+) cells. Furthermore, heterozygous(+/-) mice exhibited a high incidence of hepatocellular carcinoma after one year compared to wild-type mice, even though no significant differences in the incidence of other tumors such as lung adenocarcinoma and lymphoma were observed. Taken together, these results strongly suggest that NBS1 heterozygosity and reduced NBSI expression induces formation of specific tumors in mice.},
doi = {10.2172/943450},
journal = {},
number = ,
volume = ,
place = {United States},
year = {2002},
month = {4}
}