RRC ID 2440
Author Sumi T, Tsuneyoshi N, Nakatsuji N, Suemori H.
Title Apoptosis and differentiation of human embryonic stem cells induced by sustained activation of c-Myc.
Journal Oncogene
Abstract Embryonic stem (ES) cells are self-renewing, pluripotent cell lines, characterized by their potential to differentiate into all cell types. The proto-oncogene product c-Myc has a crucial role in the self-renewal of mouse ES (mES) cells, but its role in human ES (hES) cells is unknown. To investigate c-Myc functions in hES cells, we expressed an inducible c-Myc fused to the hormone-binding domain of the estrogen receptor (c-MycER) protein that is activated by 4-hydroxy-tamoxifen. In contrast to its role in mES cells, activation of c-MycER in hES cells induced apoptosis and differentiation into extraembryonic endoderm and trophectoderm lineages concomitant with reduced expression of the pluripotent markers Oct4 and Nanog. Neither inhibition of caspase activity nor knockdown of p53 by RNA interference impaired the induction of differentiation markers induced by c-Myc activation. In addition, differentiation induced by c-Myc activation was associated with downregulation of alpha6 integrin expression, suggesting an important role for the integrin/extracellular matrix interaction in the regulation of ES cell behavior. None of these effects occurred with deletion of the c-Myc transactivation domain, indicating that c-Myc promotes both apoptosis and differentiation in a transcriptional activity-dependent manner. Together, our results provide new insights into the c-Myc functions regulating hES cell fate.
Volume 26(38)
Pages 5564-76
Published 2007-8-16
DOI 10.1038/sj.onc.1210353
PII 1210353
PMID 17369859
MeSH Apoptosis / drug effects Apoptosis / genetics Apoptosis / physiology* Binding Sites / genetics Blotting, Western Cell Adhesion Molecules / genetics Cell Adhesion Molecules / metabolism Cell Differentiation / drug effects Cell Differentiation / genetics Cell Differentiation / physiology* Cell Line Cyclin A / genetics Cyclin A / metabolism Cyclin A1 Cyclin A2 Embryonic Stem Cells / cytology Embryonic Stem Cells / metabolism Embryonic Stem Cells / physiology* Estrogen Antagonists Fibroblast Growth Factor 2 / pharmacology Gene Expression / drug effects Hormones / metabolism Humans Microscopy, Fluorescence Proto-Oncogene Proteins c-myc / genetics Proto-Oncogene Proteins c-myc / metabolism Proto-Oncogene Proteins c-myc / physiology* RNA Interference Receptors, Estrogen / genetics Recombinant Fusion Proteins / genetics Recombinant Fusion Proteins / metabolism Recombinant Fusion Proteins / physiology Reverse Transcriptase Polymerase Chain Reaction Tamoxifen / analogs & derivatives Tamoxifen / pharmacology Transfection Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism
IF 7.971
Times Cited 61
Human embryonic stem cells KhES-2 KhES-3