Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Sep 13;91(19):8969–8973. doi: 10.1073/pnas.91.19.8969

A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors.

R Fodde 1, W Edelmann 1, K Yang 1, C van Leeuwen 1, C Carlson 1, B Renault 1, C Breukel 1, E Alt 1, M Lipkin 1, P M Khan 1, et al.
PMCID: PMC44728  PMID: 8090754

Abstract

Germ-line mutations in the human adenomatous polyposis coli (APC) gene result in familial adenomatous polyposis, an autosomal dominant disorder characterized by the early onset of multiple adenomatous polyps in the large bowel with a high likelihood of developing colorectal carcinomas. To understand the role of APC in intestinal tumor formation, we have introduced a chain-termination mutation in the 15th exon of the mouse Apc gene and employed it to modify the endogenous gene by homologous recombination in embryonic stem cells. Mice which are heterozygous for the Apc gene modification progressively develop intestinal tumors in a manner that is similar to that observed in patients with familial adenomatous polyposis and in mice which carry a mutation called multiple intestinal neoplasia (Min). Our results indicate that the Apc gene modification is a critical event in the initiation of intestinal tumor formation and results in an autosomal dominant predisposition toward development of spontaneous colonic and intestinal tumors in mice.

Full text

PDF
8972

Images in this article

8970Image
on p.8970
8971Image
on p.8971
8971Image
on p.8971
8972Image
on p.8972

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Auffray C., Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. doi: 10.1111/j.1432-1033.1980.tb06030.x. [DOI] [PubMed] [Google Scholar]
  2. Bodmer W. F., Bailey C. J., Bodmer J., Bussey H. J., Ellis A., Gorman P., Lucibello F. C., Murday V. A., Rider S. H., Scambler P. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987 Aug 13;328(6131):614–616. doi: 10.1038/328614a0. [DOI] [PubMed] [Google Scholar]
  3. Bourne H. R. Colon cancer. Suppression with a difference. Nature. 1991 Oct 24;353(6346):696–697. doi: 10.1038/353696b0. [DOI] [PubMed] [Google Scholar]
  4. Dietrich W. F., Lander E. S., Smith J. S., Moser A. R., Gould K. A., Luongo C., Borenstein N., Dove W. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell. 1993 Nov 19;75(4):631–639. doi: 10.1016/0092-8674(93)90484-8. [DOI] [PubMed] [Google Scholar]
  5. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759–767. doi: 10.1016/0092-8674(90)90186-i. [DOI] [PubMed] [Google Scholar]
  6. Fodde R., van der Luijt R., Wijnen J., Tops C., van der Klift H., van Leeuwen-Cornelisse I., Griffioen G., Vasen H., Khan P. M. Eight novel inactivating germ line mutations at the APC gene identified by denaturing gradient gel electrophoresis. Genomics. 1992 Aug;13(4):1162–1168. doi: 10.1016/0888-7543(92)90032-n. [DOI] [PubMed] [Google Scholar]
  7. Groden J., Thliveris A., Samowitz W., Carlson M., Gelbert L., Albertsen H., Joslyn G., Stevens J., Spirio L., Robertson M. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991 Aug 9;66(3):589–600. doi: 10.1016/0092-8674(81)90021-0. [DOI] [PubMed] [Google Scholar]
  8. Horii A., Nakatsuru S., Miyoshi Y., Ichii S., Nagase H., Ando H., Yanagisawa A., Tsuchiya E., Kato Y., Nakamura Y. Frequent somatic mutations of the APC gene in human pancreatic cancer. Cancer Res. 1992 Dec 1;52(23):6696–6698. [PubMed] [Google Scholar]
  9. Ichii S., Horii A., Nakatsuru S., Furuyama J., Utsunomiya J., Nakamura Y. Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP). Hum Mol Genet. 1992 Sep;1(6):387–390. doi: 10.1093/hmg/1.6.387. [DOI] [PubMed] [Google Scholar]
  10. Ichii S., Takeda S., Horii A., Nakatsuru S., Miyoshi Y., Emi M., Fujiwara Y., Koyama K., Furuyama J., Utsunomiya J. Detailed analysis of genetic alterations in colorectal tumors from patients with and without familial adenomatous polyposis (FAP). Oncogene. 1993 Sep;8(9):2399–2405. [PubMed] [Google Scholar]
  11. Joslyn G., Richardson D. S., White R., Alber T. Dimer formation by an N-terminal coiled coil in the APC protein. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11109–11113. doi: 10.1073/pnas.90.23.11109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kemler R. From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet. 1993 Sep;9(9):317–321. doi: 10.1016/0168-9525(93)90250-l. [DOI] [PubMed] [Google Scholar]
  13. Kinzler K. W., Nilbert M. C., Su L. K., Vogelstein B., Bryan T. M., Levy D. B., Smith K. J., Preisinger A. C., Hedge P., McKechnie D. Identification of FAP locus genes from chromosome 5q21. Science. 1991 Aug 9;253(5020):661–665. doi: 10.1126/science.1651562. [DOI] [PubMed] [Google Scholar]
  14. Knudson A. G., Jr Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 1985 Apr;45(4):1437–1443. [PubMed] [Google Scholar]
  15. Leppert M., Burt R., Hughes J. P., Samowitz W., Nakamura Y., Woodward S., Gardner E., Lalouel J. M., White R. Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med. 1990 Mar 29;322(13):904–908. doi: 10.1056/NEJM199003293221306. [DOI] [PubMed] [Google Scholar]
  16. Miyoshi Y., Ando H., Nagase H., Nishisho I., Horii A., Miki Y., Mori T., Utsunomiya J., Baba S., Petersen G. Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4452–4456. doi: 10.1073/pnas.89.10.4452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Miyoshi Y., Nagase H., Ando H., Horii A., Ichii S., Nakatsuru S., Aoki T., Miki Y., Mori T., Nakamura Y. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet. 1992 Jul;1(4):229–233. doi: 10.1093/hmg/1.4.229. [DOI] [PubMed] [Google Scholar]
  18. Moser A. R., Dove W. F., Roth K. A., Gordon J. I. The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J Cell Biol. 1992 Mar;116(6):1517–1526. doi: 10.1083/jcb.116.6.1517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Moser A. R., Pitot H. C., Dove W. F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 1990 Jan 19;247(4940):322–324. doi: 10.1126/science.2296722. [DOI] [PubMed] [Google Scholar]
  20. Nagase H., Miyoshi Y., Horii A., Aoki T., Ogawa M., Utsunomiya J., Baba S., Sasazuki T., Nakamura Y. Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res. 1992 Jul 15;52(14):4055–4057. [PubMed] [Google Scholar]
  21. Nakatsuru S., Yanagisawa A., Ichii S., Tahara E., Kato Y., Nakamura Y., Horii A. Somatic mutation of the APC gene in gastric cancer: frequent mutations in very well differentiated adenocarcinoma and signet-ring cell carcinoma. Hum Mol Genet. 1992 Nov;1(8):559–563. doi: 10.1093/hmg/1.8.559. [DOI] [PubMed] [Google Scholar]
  22. Nishisho I., Nakamura Y., Miyoshi Y., Miki Y., Ando H., Horii A., Koyama K., Utsunomiya J., Baba S., Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 1991 Aug 9;253(5020):665–669. doi: 10.1126/science.1651563. [DOI] [PubMed] [Google Scholar]
  23. Olschwang S., Laurent-Puig P., Groden J., White R., Thomas G. Germ-line mutations in the first 14 exons of the adenomatous polyposis coli (APC) gene. Am J Hum Genet. 1993 Feb;52(2):273–279. [PMC free article] [PubMed] [Google Scholar]
  24. Paul P., Letteboer T., Gelbert L., Groden J., White R., Coppes M. J. Identical APC exon 15 mutations result in a variable phenotype in familial adenomatous polyposis. Hum Mol Genet. 1993 Jul;2(7):925–931. doi: 10.1093/hmg/2.7.925. [DOI] [PubMed] [Google Scholar]
  25. Powell S. M., Zilz N., Beazer-Barclay Y., Bryan T. M., Hamilton S. R., Thibodeau S. N., Vogelstein B., Kinzler K. W. APC mutations occur early during colorectal tumorigenesis. Nature. 1992 Sep 17;359(6392):235–237. doi: 10.1038/359235a0. [DOI] [PubMed] [Google Scholar]
  26. Rubinfeld B., Souza B., Albert I., Müller O., Chamberlain S. H., Masiarz F. R., Munemitsu S., Polakis P. Association of the APC gene product with beta-catenin. Science. 1993 Dec 10;262(5140):1731–1734. doi: 10.1126/science.8259518. [DOI] [PubMed] [Google Scholar]
  27. Smith K. J., Johnson K. A., Bryan T. M., Hill D. E., Markowitz S., Willson J. K., Paraskeva C., Petersen G. M., Hamilton S. R., Vogelstein B. The APC gene product in normal and tumor cells. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2846–2850. doi: 10.1073/pnas.90.7.2846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Spirio L., Olschwang S., Groden J., Robertson M., Samowitz W., Joslyn G., Gelbert L., Thliveris A., Carlson M., Otterud B. Alleles of the APC gene: an attenuated form of familial polyposis. Cell. 1993 Dec 3;75(5):951–957. doi: 10.1016/0092-8674(93)90538-2. [DOI] [PubMed] [Google Scholar]
  29. Su L. K., Johnson K. A., Smith K. J., Hill D. E., Vogelstein B., Kinzler K. W. Association between wild type and mutant APC gene products. Cancer Res. 1993 Jun 15;53(12):2728–2731. [PubMed] [Google Scholar]
  30. Su L. K., Kinzler K. W., Vogelstein B., Preisinger A. C., Moser A. R., Luongo C., Gould K. A., Dove W. F. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science. 1992 May 1;256(5057):668–670. doi: 10.1126/science.1350108. [DOI] [PubMed] [Google Scholar]
  31. Su L. K., Vogelstein B., Kinzler K. W. Association of the APC tumor suppressor protein with catenins. Science. 1993 Dec 10;262(5140):1734–1737. doi: 10.1126/science.8259519. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES