TY - JOUR
T1 - Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression
AU - Kucherlapati, Melanie
AU - Yang, Kan
AU - Kuraguchi, Mari
AU - Zhao, Jie
AU - Lia, Maria
AU - Heyer, Joerg
AU - Kane, Michael F.
AU - Fan, Kunhua
AU - Russell, Robert
AU - Brown, Anthony M.C.
AU - Kneitz, Burkhard
AU - Edelmann, Winfried
AU - Kolodner, Richard D.
AU - Lipkin, Martin
AU - Kucherlapati, Raju
PY - 2002/7/23
Y1 - 2002/7/23
N2 - Flap endonuclease (Fen1) is required for DNA replication and repair, and defects in the gene encoding Fen1 cause increased accumulation of mutations and genome rearrangements. Because mutations in some genes involved in these processes cause cancer predisposition, we investigated the possibility that Fen1 may function in tumorigenesis of the gastrointestinal tract. Using gene knockout approaches, we introduced a null mutation into murine Fen1. Mice homozygous for the Fen1 mutation were not obtained, suggesting absence of Fen1 expression leads to embryonic lethality. Most Fen1 heterozygous animals appear normal. However, when combined with a mutation in the adenomatous polyposis coli (Apc) gene, double heterozygous animals have increased numbers of adenocarcinomas and decreased survival. The tumors from these mice show microsatellite instability. Because one copy of the Fen1 gene remained intact in tumors, Fen1 haploinsufficiency appears to lead to rapid progression of cancer.
AB - Flap endonuclease (Fen1) is required for DNA replication and repair, and defects in the gene encoding Fen1 cause increased accumulation of mutations and genome rearrangements. Because mutations in some genes involved in these processes cause cancer predisposition, we investigated the possibility that Fen1 may function in tumorigenesis of the gastrointestinal tract. Using gene knockout approaches, we introduced a null mutation into murine Fen1. Mice homozygous for the Fen1 mutation were not obtained, suggesting absence of Fen1 expression leads to embryonic lethality. Most Fen1 heterozygous animals appear normal. However, when combined with a mutation in the adenomatous polyposis coli (Apc) gene, double heterozygous animals have increased numbers of adenocarcinomas and decreased survival. The tumors from these mice show microsatellite instability. Because one copy of the Fen1 gene remained intact in tumors, Fen1 haploinsufficiency appears to lead to rapid progression of cancer.
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U2 - 10.1073/pnas.152321699
DO - 10.1073/pnas.152321699
M3 - Article
C2 - 12119409
AN - SCOPUS:0037162498
SN - 0027-8424
VL - 99
SP - 9924
EP - 9929
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 15
ER -