The threshold level of adenomatous polyposis coli protein for mouse intestinal tumorigenesis.

The adenomatous polyposis coli (APC) gene, whose mutations are responsible for familial adenomatous polyposis, is a major negative controller of the Wnt/beta-catenin pathway. To investigate the dose-dependent effects of APC protein in suppressing intestinal tumorigenesis, we constructed mutant mice carrying hypomorphic Apc alleles Apc(neoR) and Apc(neoF) whose expression levels were reduced to 20% and 10% of the wild type, respectively. Although both hypomorphic heterozygotes developed intestinal polyps, tumor multiplicities were much lower than that in Apc(Delta716) mice, heterozygotes of an Apc null allele. Like in Apc(Delta716) mice, loss of the wild-type Apc allele was confirmed for all polyps examined in the Apc(neoR) and Apc(neoF) mice. In the embryonic stem cells homozygous for these hypomorphic Apc alleles, the level of the APC protein was inversely correlated with both the beta-catenin accumulation and beta-catenin/T-cell factor transcriptional activity. These results suggest that the reduced APC protein level increases intestinal polyp multiplicity through quantitative stimulation of the beta-catenin/T-cell factor transcription. We further estimated the threshold of APC protein level that forms one polyp per mouse as approximately 15% of the wild type. These results also suggest therapeutic implications concerning Wnt signaling inhibitors.

[1]  Ossama Tawfik,et al.  BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt–β-catenin signaling , 2004, Nature Genetics.

[2]  M. Taketo.  Shutting down Wnt signal–activated cancer , 2004, Nature Genetics.

[3]  Wei Dong Chen,et al.  Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer , 2004, Nature Genetics.

[4]  Makoto M Taketo,et al.  Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Δ716 Cdx2+/− compound mutant mice , 2003, Nature Genetics.

[5]  M. Taketo,et al.  Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinal polyposis. , 2003, Cancer research.

[6]  Hans Clevers,et al.  Caught up in a Wnt storm: Wnt signaling in cancer. , 2003, Biochimica et biophysica acta.

[7]  Makoto M Taketo,et al.  Requirement for tumor suppressor Apc in the morphogenesis of anterior and ventral mouse embryo. , 2003, Developmental biology.

[8]  Joanna Groden,et al.  Attenuated APC alleles produce functional protein from internal translation initiation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Peter K. Sorger,et al.  A role for the Adenomatous Polyposis Coli protein in chromosome segregation , 2001, Nature Cell Biology.

[10]  H. Clevers,et al.  Mutations in the APC tumour suppressor gene cause chromosomal instability , 2001, Nature Cell Biology.

[11]  O. Sieber,et al.  The adenomatous polyposis coli (APC) tumour suppressor--genetics, function and disease. , 2000, Molecular medicine today.

[12]  K. Kinzler,et al.  Analysis of masked mutations in familial adenomatous polyposis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Leppert,et al.  Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps , 1998, Nature Genetics.

[14]  P. Polakis.  The adenomatous polyposis coli (APC) tumor suppressor. , 1997, Biochimica et biophysica acta.

[15]  Bruno C. Hancock,et al.  Suppression of Intestinal Polyposis in Apc Δ716 Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2) , 1996, Cell.

[16]  M. Taketo,et al.  Evidence against dominant negative mechanisms of intestinal polyp formation by Apc gene mutations. , 1995, Cancer research.

[17]  M Oshima,et al.  Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[18]  R Fodde,et al.  A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[19]  G. Thomas,et al.  Alleles of the APC gene: An attenuated form of familial polyposis , 1993, Cell.

[20]  Bert Vogelstein,et al.  APC mutations occur early during colorectal tumorigenesis , 1992, Nature.

[21]  H. Pitot,et al.  A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. , 1990, Science.

[22]  K. Haigis,et al.  A Robertsonian translocation suppresses a somatic recombination pathway to loss of heterozygosity , 2003, Nature Genetics.

[23]  R. Fodde,et al.  Apc modulates embryonic stem-cell differentiation by controlling the dosage of β-catenin signaling , 2003, Nature Genetics.

[24]  K. Kinzler,et al.  Small changes in expression affect predisposition to tumorigenesis , 2002, Nature Genetics.