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 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.
Holm
Teresa M
TM
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, Boston, USA.
Jackson-Grusby
Laurie
L
Brambrink
Tobias
T
Yamada
Yasuhiro
Y
Rideout
William M
WM
Jaenisch
Rudolf
R
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
D017931:DNA Primers