Tumor progression in Apc1638N mice with Exo1 and Fen1 deficiencies

M. Kucherlapati, A. Nguyen, M. Kuraguchi, K. Yang, K. Fan, R. Bronson, K. Wei, M. Lipkin, W. Edelmann, R. Kucherlapati

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Flap endonuclease 1 (Fen1) and exonuclease 1 (Exo1) have sequence homology and similar nuclease capabilities. Both function in multiple pathways of DNA metabolism, but appear to have distinct in vivo nucleic acid substrates, and therefore distinct metabolic roles. When combined with Apc1638N, Fen1 promotes tumor progression. Because of functional similarity to Fen1, and because Exo1 is involved in DNA mismatch repair (MMR) by interaction with Msh2 and Mlh1, genes that cause hereditary nonpolyposis colorectal cancer (HNPCC), we investigated the possibility that Exo1 might also act as a modifier to Apc 1638N. We present evidence that mice with combined mutations in Apc1638N and Exo1 and Apc1638N, Exo1 and Fen1 genes show moderate increased tumor incidence and multiplicity in comparison to Apc 1638N siblings, implying a low penetrance role for Exo1 in early gastrointestinal (GI) tumorigenesis. Despite a decrease in median survival (10 months) in Apc1638N Exo1 mice, their tumors do not progress any more rapidly than those of Apc1638N. Instead these animals die from infections that are the result of impaired immune response. Apc1638N Exo1 Fen1 mice survive longer (18 months), and therefore appear relatively immune competent. They die of invasive GI tumors that display microsatellite instability (MSI). Our results show that Exo1 has a modest tumor suppressor function.

Original languageEnglish (US)
Pages (from-to)6297-6306
Number of pages10
JournalOncogene
Volume26
Issue number43
DOIs
StatePublished - Sep 20 2007

Keywords

  • Apc
  • Exo1
  • Fen1
  • Mouse

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Kucherlapati, M., Nguyen, A., Kuraguchi, M., Yang, K., Fan, K., Bronson, R., Wei, K., Lipkin, M., Edelmann, W., & Kucherlapati, R. (2007). Tumor progression in Apc1638N mice with Exo1 and Fen1 deficiencies. Oncogene, 26(43), 6297-6306. https://doi.org/10.1038/sj.onc.1210453