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

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.

Lawrence Berkeley National Laboratory

关键词: Lymphomas;    Chromosomes;    59;    Lungs;    Genes;   

DOI  :  10.2172/943450
RP-ID  :  LBNL-50210
RP-ID  :  DE-AC02-05CH11231
RP-ID  :  943450

美国|英语

来源: UNT Digital Library

【 摘 要 】

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.