title: Global loss of imprinting leads to widespread tumorigenesis in adult mice.
abstract: 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 TGFbeta 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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, Boston, USA.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Holm
authors.forename: Laurie
authors.initials: L
authors.lastname: Jackson-Grusby
authors.forename: Tobias
authors.initials: T
authors.lastname: Brambrink
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: William M
authors.initials: WM
authors.lastname: Rideout
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
mesh_terms: D000818:Animals; D001483:Base Sequence; D002461:Cell Line, Transformed; D019175:DNA Methylation; D017931:DNA Primers; D018392:Genomic Imprinting; D018095:Germ-Line Mutation; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D016133:Polymerase Chain Reaction
chemical_list: D017931:DNA Primers