Haploinsufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression.

Proc Natl Acad Sci U S A 2002 Jul 15;99(15):9924-9. Epub 2002 Jul 15.

Department of Medicine and Harvard Partners Center for Genetics and Genomics, Harvard Medical School, Boston, MA 02115, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.152321699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC126601PMC
July 2002
9 Reads

Publication Analysis

Top Keywords

fen1
10
endonuclease fen1
8
flap endonuclease
8
heterozygous animals
8
expression leads
4
leads embryonic
4
fen1 expression
4
absence fen1
4
suggesting absence
4
embryonic lethality
4
lethality fen1
4
appear normal
4
combined mutation
4
animals appear
4
mutation suggesting
4
fen1 heterozygous
4
normal combined
4
homozygous fen1
4
gene knockout
4
knockout approaches
4

Altmetric Statistics

References

(Supplied by CrossRef)

Yang et al.
The Journal of experimental zoology 1997

Bodmer et al.
Nature; Physical Science (London) 1987

Leppert et al.
Science 1987

Groden et al.
Cell 1991

Nishisho et al.
Science 1991

Kinzler et al.
Science 1991

Kuismanen et al.
American Journal Of Pathology 2000

Peltomaki et al.
Gastroenterology 1997

Peltomaki et al.
Human Molecular Genetics 2001

Peltom  ki et al.
Mutation Research 2001

Wheeler et al.
Journal of Medical Genetics 2000

Similar Publications