The overall objective of this research proposal is to understand the mechanism by which epigenetic processes such as DNA methylation can contribute to neoplasia. We wish to investigate a direct causal role for DNMT1, the major mammalian maintenance DNA (cytosine-5) methyltransferase, in inducing C-T transition mutations similar to that shown for bacterial (cytosine-5) methyltransferases. This will involve the creation of conditional and tissue-specific alleles of DNMT 1 and the generation of transgenic mice and primary murine embryonic fibroblast (MEFs) cell lines using the established Cre/LoxP or Flp/Frt system and standard genetic methods. We will define the role of Dnmt1 in the incidence of point mutations in MEFs harboring the various conditional alleles by performing a quantitative analysis that measures spontaneous and induced mutation frequencies. We will then analyze wild-type and tumor prone mice that contain tissue-specific and conditional alleles of DNMT1 for the incidence of genomic methylation, incidence of point mutations, and tumor formation. These studies may provide a novel paradigm for understanding events that lead to abnormal cellular proliferation.
| Tripathi, Manish K; Deane, Natasha G; Zhu, Jing et al. (2014) Nuclear factor of activated T-cell activity is associated with metastatic capacity in colon cancer. Cancer Res 74:6947-57 |
| Seeley, Erin H; Washington, Mary K; Caprioli, Richard M et al. (2013) Proteomic patterns of colonic mucosal tissues delineate Crohn's colitis and ulcerative colitis. Proteomics Clin Appl 7:541-9 |
| Al-Greene, Nicole T; Means, Anna L; Lu, Pengcheng et al. (2013) Four jointed box 1 promotes angiogenesis and is associated with poor patient survival in colorectal carcinoma. PLoS One 8:e69660 |
| Cao, Yi; Kumar, Roshan M; Penn, Bennett H et al. (2006) Global and gene-specific analyses show distinct roles for Myod and Myog at a common set of promoters. EMBO J 25:502-11 |
| Boyer, Laurie A; Lee, Tong Ihn; Cole, Megan F et al. (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947-56 |
