Abstract
The adenomatous polyposis coli (APC) gene product is mutated in the vast majority of human colorectal cancers. APC negatively regulates the WNT pathway by aiding in the degradation of β-catenin, which is the transcription factor activated downstream of WNT signaling. APC mutations result in β-catenin stabilization and constitutive WNT pathway activation, leading to aberrant cellular proliferation. APC mutations associated with colorectal cancer commonly fall in a region of the gene termed the mutation cluster region and result in expression of an N-terminal fragment of the APC protein. Biochemical and molecular studies have revealed localization of APC/Apc to different sub-cellular compartments and various proteins outside of the WNT pathway that associate with truncated APC/Apc. These observations and genotype–phenotype correlations have led to the suggestion that truncated APC bears neomorphic and/or dominant-negative function that support tumor development. To analyze this possibility, we have generated a novel allele of Apc in the mouse that yields complete loss of Apc protein. Our studies reveal that whole-gene deletion of Apc results in more rapid tumor development than the APC multiple intestinal neoplasia (ApcMin) truncation. Furthermore, we found that adenomas bearing truncated Apc had increased β-catenin activity when compared with tumors lacking Apc protein, which could lead to context-dependent inhibition of tumorigenesis.
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References
Albuquerque C, Breukel C, van der Luijt R, Fidalgo P, Lage P, Slors FJM et al. (2002). The ‘just-right’ signaling model: APC somatic mutations are selected based on a specific level of activation of the beta-catenin signaling cascade. Hum Mol Genet 11: 1549–1560.
Aoki K, Taketo M . (2007). Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene. J Cell Sci 120: 3327–3335.
Clevers H . (2006). Wnt/beta-catenin signaling in development and disease. Cell 127: 469–480.
Colnot S, Niwa-Kawakita M, Hamard G, Godard C, Le Plenier S, Houbron C et al. (2004). Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers. Lab Invest 84: 1619–1630.
Courtois-Cox S, Jones SL, Cichowski K . (2008). Many roads lead to oncogene-induced senescence. Oncogene 27: 2801–2809.
Damalas A, Kahan S, Shtutman M, Ben-Ze'ev A, Oren M . (2001). Deregulated beta-catenin induces a p53- and ARF-dependent growth arrest and cooperates with Ras in transformation. EMBOJ 20: 4912–4922.
de la Chapelle A . (2004). Genetic predisposition to colorectal cancer. Nat Rev Cancer 4: 769–780.
el Marjou F, Janssen KP, Chang BH, Li M, Hindie V, Chan L et al. (2004). Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39: 186–193.
Fodde R, Smits R . (2001). Disease model: familial adenomatous polyposis. Trends Mol Med 7: 369–373.
Fodde R, Smits R, Clevers H . (2001). APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 1: 55–67.
Gaspar C, Franken P, Molenaar L, Breukel C, Van Der Valk M, Smits R et al. (2009). A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis. PLoS Genet 5: e1000547.
Gherzi R, Trabucchi M, Ponassi M, Ruggiero T, Corte G, Moroni C et al. (2007). The RNA-binding protein KSRP promotes decay of beta-catenin mRNA and is inactivated by PI3K-AKT signaling. PLoS Biol 5.
Giles R . (2003). Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta (BBA) Rev Cancer 1653: 1–24.
Haigis K, Hoff PD, White A, Shoemaker AR, Halberg RB, Dove W . (2004). Tumor regionality in the mouse intestine reflects the mechanism of loss of Apc function. Proc Natl Acad Sci USA 101: 9769–9773.
Haigis K, Kendall K, Wang Y, Cheung A, Haigis M, Glickman J et al. (2008). Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet 40: 600–608.
Harada N, Tamai Y, Ishikawa T, Sauer B, Takaku K, Oshima M et al. (1999). Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBOJ 18: 5931–5942.
Herrera L, Kakati S, Gibas L, Pietrzak E, Sandberg AA . (1986). Gardner syndrome in a man with an interstitial deletion of 5q. Am J Med Genet 25: 473–476.
Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F . (2002). Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 22: 1172–1183.
Kinzler KW, Vogelstein B . (1996). Lessons from hereditary colorectal cancer. Cell 87: 159–170.
Lamlum H, Ilyas M, Rowan A, Clark S, Johnson V, Bell J et al. (1999). The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's ‘two-hit’ hypothesis. Nat Med 5: 1071–1075.
Mccartney B, Nathke I . (2008). Cell regulation by the Apc protein Apc as master regulator of epithelia. Curr Opin Cell Biol 20: 186–193.
Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B et al. (1997). Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275: 1787–1790.
Nathke I . (2004). APC at a glance. J Cell Sci. 117: 4873–4875.
Nieuwenhuis MH, Vasen HF . (2007). Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol 61: 153–161.
Oshima M, Oshima H, Kitagawa K, Kobayashi M, Itakura C, Taketo M . (1995). Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proc Natl Acad Sci USA 92: 4482–4486.
Pollard P, Deheragoda M, Segditsas S, Lewis A, Rowan A, Howarth K et al. (2009). The Apc 1322T mouse develops severe polyposis associated with submaximal nuclear beta-catenin expression. Gastroenterology 136: 2204–2213 e1–13.
Sieber OM, Lamlum H, Crabtree MD, Rowan AJ, Barclay E, Lipton L et al. (2002). Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or ‘multiple’ colorectal adenomas. Proc Natl Acad Sci USA 99: 2954–2958.
Smits R, Kielman MF, Breukel C, Zurcher C, Neufeld K, Jagmohan-Changur S et al. (1999). Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes Dev 13: 1309–1321.
Soravia C, Berk T, Madlensky L, Mitri A, Cheng H, Gallinger S et al. (1998). Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 62: 1290–1301.
Su LK, Kinzler KW, Vogelstein B, Preisinger AC, Moser AR, Luongo C et al. (1992). Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256: 668–670.
Takacs C, Baird J, Hughes E, Kent S, Benchabane H, Paik R et al. (2008). Dual positive and negative regulation of wingless signaling by adenomatous polyposis coli. Science 319: 333–336.
Tallquist MD, Soriano P . (2000). Epiblast-restricted Cre expression in MORE mice: a tool to distinguish embryonic vs. extra-embryonic gene function. Genesis 26: 113–115.
Acknowledgements
We thank members of the Jacks labs, Keara Lane in particular, for experimental advice and assistance. This work was supported by the Howard Hughes Medical Institute and partially by the Cancer Center Support (core) Grant P30-CA14051 from the National Cancer Institute. TJ is a Howard Hughes Investigator and a Daniel K Ludwig Scholar.
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Cheung, A., Carter, A., Kostova, K. et al. Complete deletion of Apc results in severe polyposis in mice. Oncogene 29, 1857–1864 (2010). https://doi.org/10.1038/onc.2009.457
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DOI: https://doi.org/10.1038/onc.2009.457
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