Apoptosis and differentiation of human embryonic stem cells induced by sustained activation of c-Myc

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 a6 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.

Epigenome and chromatin structure in human embryonic stem cells undergoing differentiation

“…3C andBártová et al, 2008). This supports the conclusion that not all aspects of the structural and functional biology of mouse and human ESCs are similar (Constantinescu et al, 2006;Sumi et al, 2007).…”

“…However, c-myc is probably not important for self-renewal of hESCs. Rather, it induces apoptosis and differentiation of these cells (Sumi et al, 2007). This idea is supported by our recent finding that, contrary to Oct3/4, which is responsible for hESCs pluripotency, c-myc localizes to the periphery of its related chromosome territory in both pluripotent and differentiated hESCs (Bár-tová et al, 2008).…”

Sphingomyelin synthase 2 overexpression promotes cisplatin‑induced apoptosis of HepG2 cells

“…c-Myc is a proto-oncogene which is a key regulator of cell proliferation, apoptosis and cellular differentiation (17). However, in the present study, the expression of SMS2 was able to upregulate the expression of c-Myc, which would lead to the viability of HepG2 cells.…”

Apoptosis: Reprogramming and the Fate of Mature Cells

“…A major concern of iPSCbased therapy is the tumorigenicity of iPSC, particularly for the risk of overexpressing Klf4 and c-Myc, both of them are known oncogenes [67]. The latter has been found to induce apoptosis and differentiation in human ESC and trigger cellular senescence during reprogramming [38]. Additionally, the pivotal role of p53 activation during reprogramming appears to be a self-defense mechanism that prevents cells from oncogenic transformation.…”

“…Interference with this regulatory circuitry may lead to apoptosis, differentiation, or cell senescence in ESC cultures. A recent study of hESCs demonstrated that sustained activation of the oncogene c-Myc induces apoptosis via activation of caspase and triggers differentiation by reduction of Oct4 and Nanog expression [38].…”