Geminin Is Essential for Pluripotent Cell Viability During Teratoma Formation, but Not for Differentiated Cell Viability During Teratoma Expansion.
Pluripotent embryonic stem cells (ESCs) are unusual in that geminin has been reported to be essential either to prevent differentiation by maintaining expression of pluripotency genes or to prevent DNA rereplication-dependent apoptosis. To distinguish between these two incompatible hypotheses, immune-compromised mice were inoculated subcutaneously with ESCs harboring conditional Gmnn alleles alone or together with a tamoxifen-dependent Cre recombinase gene. Mice were then injected with tamoxifen at various times during which the ESCs proliferated and differentiated into a teratoma. For comparison, the same ESCs were cultured in vitro in the presence of monohydroxytamoxifen. The results revealed that geminin is a haplosufficient gene that is essential for ESC viability before they differentiate into a teratoma, but once a teratoma is established, the differentiated cells can continue to proliferate in the absence of Gmnn alleles, geminin protein, and pluripotent stem cells. Thus, differentiated cells did not require geminin for efficient proliferation within the context of a solid tissue, although they did when teratoma cells were cultured in vitro. These results provide proof-of-principle that preventing geminin function could prevent malignancy in tumors derived from pluripotent cells by selectively eliminating the progenitor cells with little harm to normal cells.
1 Eunice Kennedy Shriver National Institute of Child Health and Human Development , Bethesda, Maryland.
Diane C
DC
Adler-Wailes
2 Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc. , Bethesda, Maryland.
Joshua A
JA
Kramer
1 Eunice Kennedy Shriver National Institute of Child Health and Human Development , Bethesda, Maryland.
Melvin L
ML
DePamphilis
D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004261:DNA Replication / Q000235:genetics; D005260:Female; D064248:Geminin / Q000378:metabolism*; D017353:Gene Deletion; D057895:Haploinsufficiency / Q000235:genetics; D019426:Integrases / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000066450:Mouse Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D013724:Teratoma / Q000378:metabolism* / Q000473:pathology*
D064248:Geminin; C577997:Gmnn protein, mouse; D019394:Ki-67 Antigen; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D013629:Tamoxifen; C045073:Cre recombinase; D019426:Integrases
DNA rereplication; embryonal carcinoma cells; embryonic stem cells; geminin; germ cell neoplasia; teratocarcinoma