Abstract

The focus of this proposal is to define the role of DNA methylation in development and cancer. We will investigate the influence of DNA methylation on the expression of determination and transforming genes and study interactions between them, determine how methylation patterns evolve during tumor progression and test the hypothesis that DNA methylation can skew the genetics of some human cancers. Cells of the mouse embryo cell line 10T1/2 primed to differentiate with 5-azacytidine, will be used to investigate hierarchies of gene control in mesenchymal determination and differentiation. I am particularly interested in defining the role of methylcytosine in this process. The influence of cellular determination on oncogenesis and the interplay between transforming and determination genes will ge investigated in the same system. The potential for DNA methylation to silence transforming genes will be examined by the molecular cloning and characterization of a novel oncogene in human osteogenic sarcoma cells treated with 5- azadeoxycytidine. Changes in methylation levels and patterns during tumor progression will be tracked in fresh samples of human bladder tumors. The possibility that allele specific methylation of human genes can skew the genetics of human cancer, due to the inherent mutagenic activity of 5-methylcytosine, will be examined in human retinoblastoma and Wilms' tumor.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA049758-03
Application #
3479759
Study Section
Special Emphasis Panel (SRC (88))
Project Start
1989-05-01
Project End
1996-04-30
Budget Start
1991-05-01
Budget End
1992-04-30
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of Southern California
Department
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Kelly, Theresa K; De Carvalho, Daniel D; Jones, Peter A (2010) Epigenetic modifications as therapeutic targets. Nat Biotechnol 28:1069-78
Kelly, Theresa K; Miranda, Tina Branscombe; Liang, Gangning et al. (2010) H2A.Z maintenance during mitosis reveals nucleosome shifting on mitotically silenced genes. Mol Cell 39:901-11
Gonzalgo, Mark L; Jones, Peter A (2002) Quantitative methylation analysis using methylation-sensitive single-nucleotide primer extension (Ms-SNuPE). Methods 27:128-33
Nguyen, C; Liang, G; Nguyen, T T et al. (2001) Susceptibility of nonpromoter CpG islands to de novo methylation in normal and neoplastic cells. J Natl Cancer Inst 93:1465-72
Pao, M M; Tsutsumi, M; Liang, G et al. (2001) The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cells. Hum Mol Genet 10:903-10
Nguyen, C T; Gonzales, F A; Jones, P A (2001) Altered chromatin structure associated with methylation-induced gene silencing in cancer cells: correlation of accessibility, methylation, MeCP2 binding and acetylation. Nucleic Acids Res 29:4598-606
Pao, M M; Liang, G; Tsai, Y C et al. (2000) DNA methylator and mismatch repair phenotypes are not mutually exclusive in colorectal cancer cell lines. Oncogene 19:943-52
Robertson, K D; Jones, P A (2000) DNA methylation: past, present and future directions. Carcinogenesis 21:461-7
Jones, P A (1999) The DNA methylation paradox. Trends Genet 15:34-7
Robertson, K D; Uzvolgyi, E; Liang, G et al. (1999) The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 27:2291-8

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