Suppression of Indued Pluripotent Stem Cell Generation by the p53-p21 Pathway
By Hyenjong Hong, Kazutoshi Takahashi, T. Ichisaka, T. Aoi, O. Kanagawa, M. Nakagawa, K. Okita, S. Yamanaka. Nature, 2009
1,358 citations recorded by the source corpus.
Induced pluripotent stem (iPS) cells can be generated from somatic cells by the introduction of Oct3/4 (also known as Pou5f1), Sox2, Klf4 and c-Myc, in mouse and in human. The efficiency of this process, however, is low. Pluripotency can be induced without c-Myc, but with even lower efficiency. A p53 (also known as TP53 in humans and Trp53 in mice) short-interfering RNA (siRNA) was recently shown to promote human iPS cell generation, but the specificity and mechanisms remain to be determined. Here we report that up to 10% of transduced mouse embryonic fibroblasts lacking p53 became iPS cells, even without the Myc retrovirus. The p53 deletion also promoted the induction of integration-free mouse iPS cells with plasmid transfection. Furthermore, in the p53-null background, iPS cells were generated from terminally differentiated T lymphocytes. The suppression of p53 also increased the efficiency of human iPS cell generation. DNA microarray analyses identified 34 p53-regulated genes that are common in mouse and human fibroblasts. Functional analyses of these genes demonstrate that the p53–p21 pathway serves as a barrier not only in tumorigenicity, but also in iPS cell generation.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/f3ac10d9669142c231d82656bc3d1e0dd6fb778e
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Citations in the corpus
- Senescence impairs successful reprogramming to pluripotent stem cells. (2009, background): “Two research groups have reported similar observations upon expression of the OSKM, OSK or SO (Hong et al., 2009) (Kawamura et al., 2009).”
- Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “Mouse and human fibroblasts silenced for p21 or p53 generate a greater number of induced pluripotent stem (iPS) cell colonies with an accelerated rate, indicating that reprogramming is more efficient when senescence is ablated (23, 162, 180, 219, 322).”
- Induced pluripotency: history, mechanisms, and applications. (2010, background): “…reprogramming is the finding that expression of the reprogramming factors in p53 or ink4a/arf-deficient immortalized fibroblasts leads to dramatic increases in reprogramming efficiency and speed (Banito et al. 2009; Hong et al. 2009; Kawamura et al. 2009; H Li et al. 2009; Utikal et al. 2009b).”
- The essence of senescence. (2010, background): “…and p53 limit the efficiency of iPS cell formation, it has been suggested that cellular senescence counteracts the induced conversion of primary cells into pluripotent stem cells (Banito et al. 2009; Hong et al. 2009; Kawamura et al. 2009; Li et al. 2009; Marión et al. 2009; Utikal et al. 2009).”
- The Cancer Stem Cell Niche: How Essential is the Niche in Regulating Stemness of Tumor Cells? (2015, neutral): “Indeed, p53 inhibition and Human telomerase reverse transcriptase (hTERT) activation (Hahn et al., 1999; Stewart et al., 2002; Hong et al., 2009) or the aberrant acquisition of stemcell-associated factors such as Neurogenic locus notch homolog (NODAL), NOTCH, and Wingless-type MMTV integration site ”
- Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. (2012, positive): “Because high proliferative capacity is essential to facilitate the reprogramming process, we selected ESC cell-cycle regulator genes (Bub1, Cdc20, Mad2l1, Ccnf) (Hong et al., 2009).”
- Emerging trends and new developments in regenerative medicine: a scientometric update (2000 – 2014) (2014, background): “Suppression of the p53 pathway has been investigated as a means of improving the efficiency of iPSC generation and reducing the likelihood of malignant tumors [15].”