Global loss of imprinting leads to widespread tumorigenesis in adult mice

Loss of imprinting (LOI), commonly observed in human tumors, refers to loss of monoallelic gene regulation normally conferred by parent-of-origin-specific DNA methylation. To test the function of LOI in tumorigenesis, we developed a model by using transient demethylation to generate imprint-free mou...

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Bibliographic Details
Published in:Cancer cell 2005-10, Vol.8 (4), p.275-285
Main Authors: Holm, Teresa M., Jackson-Grusby, Laurie, Brambrink, Tobias, Yamada, Yasuhiro, Rideout, William M., Jaenisch, Rudolf
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Cell Line, Transformed
DNA Methylation
DNA Primers
Genomic Imprinting
Germ-Line Mutation
Mice
Neoplasms, Experimental - genetics
Neoplasms, Experimental - pathology
Polymerase Chain Reaction
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Summary:Loss of imprinting (LOI), commonly observed in human tumors, refers to loss of monoallelic gene regulation normally conferred by parent-of-origin-specific DNA methylation. To test the function of LOI in tumorigenesis, we developed a model by using transient demethylation to generate imprint-free mouse embryonic stem cells (IF-ES cells). Embryonic fibroblasts derived from IF-ES cells (IF-MEFs) display TGFβ resistance and reduced p19 and p53 expression and form tumors in SCID mice. IF-MEFs exhibit spontaneous immortalization and cooperate with H-Ras in cellular transformation. Chimeric animals derived from IF-ES cells develop multiple tumors arising from the injected IF-ES cells within 12 months. These data demonstrate that LOI alone can predispose cells to tumorigenesis and identify a pathway through which immortality conferred by LOI lowers the threshold for transformation.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2005.09.007