Linking the p53 tumor suppressor pathway to somatic cell reprogramming
By Teruhisa Kawamura, Jotaro Suzuki, Yunyuan V. Wang, S. Menéndez, L. B. Morera, Á. Raya, G. Wahl, J. Belmonte. 2009
539 citations recorded by the source corpus.
Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. Here we show that reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing reprogramming-induced apoptosis in mouse fibroblasts increases reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the reprogramming efficiency of human somatic cells. These results provide insights into reprogramming mechanisms and suggest new routes to more efficient reprogramming while minimizing the use of oncogenes.
Subfields: Molecular Biology
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Citations in the corpus
- 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).”
- Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. (2010, result): “While our work was in progress, six independent laboratories identified cell senescence as a roadblock for reprogramming (Hong et al., 2009; Kawamura et al., 2009; Li et al., 2009; Marión et al., 2009; Utikal et al., 2009; Zhao et al., 2008), creating significant interest in finding compounds that a”
- The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. (2010, result): “A link between cancer and stem cells is also consistent with the observation that p53 inactivation enhances iPS reprogramming (Hong et al. 2009; Kawamura et al. 2009).”
- Mutant p53 in Cancer: New Functions and Therapeutic Opportunities (2014, background): “Wildtype p53 was characterized as a suppressor of somatic stem cell reprogramming, the process in which differentiated somatic cells can be reprogrammed into a pluripotent stem cell to allow for unlimited expansion (Kawamura et al., 2009; Marión et al., 2009).”