Linking the p53 tumour suppressor pathway to somatic cell reprogramming

Abstract

Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes1–8, but the low frequency and tendency to induce malignant transformation9 compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. We show that reprogramming factors can activate the p53 pathway. Reducing signaling to p53 by expressing a mutated version of one of its negative regulators, by deleting or silencing p53 or its target gene, p21, or by antagonizing apoptosis enhanced three factor (Oct4/Sox2/Klf4)-mediated reprogramming of mouse fibroblasts. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline transmitting chimeric mice using only Oct4 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.

Blockade of senescence‐associated micro RNA ‐195 in aged skeletal muscle cells facilitates reprogramming to produce induced pluripotent stem cells.

“…Previous reports demonstrated that age‐dependent decline in reprogramming efficiency is correlated with activated intrinsic senescence pathways in cells from old donors (Zhao et al ., 2008; Kawamura et al ., 2009; Li et al ., 2009). Reprogramming SkMs into iPSCs reverses several cellular and molecular characteristics associated with aging, including senescence, telomere truncation, mitochondrial dysfunction, and global changes in gene expression.…”

“…Another study showed that knockdown of FOXO1 reduced the reprogramming efficiency as well (Koga et al ., 2014). Additionally, the age‐dependent decline in reprogramming efficiency could be reversed by silencing p53 expression (Kawamura et al ., 2009). The present study demonstrated that both protein levels of p53 and FOXO1 dramatically change with age in SkMs and affect reprogramming efficiency.…”

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

“…Thus, overexpression of this TF has profound and lasting consequences on the expression of growth-promoting genes. This process is influenced by the p53 status Kawamura et al, 2009;Mario´n et al, 2009;Utikal et al, 2009).…”

Direct lineage conversion: induced neuronal cells and induced neural stem cells

“…The transient inhibition of the p53 pathway renders iPS cell generation more efficient in terms of the number of cells reprogrammed (Kawamura et al, 2009;Neveu et al, 2010;Okita et al, 2011), while the coexpression of Rarg (retinoid acid receptor-γ) and Lrh-1 (liver receptor homologue 1, also known as orphan nuclear receptor Nr5a2) with the four iPS cell factors greatly promoted the reprogramming efficiency (Wang et al, 2011). Furthermore, Nr5a2 can replace Oct4 in the derivation of iPS cells from mouse fibroblasts and also enhances reprogramming efficiency (Heng et al, 2010).…”

“…In contrast to iPS cell induction, iN cell reprogramming does not require a neural progenitor state; instead, it involves the direct conversion from one lineage to another different lineage, bypassing the proliferation state (Hong et al, 2009;Kawamura et al, 2009;Li et al, 2009;Marion et al, 2009;Utikal et al, 2009). Moreover, the reprogramming of iN cells provides a new approach to the study of cell fate determination, drug discovery, and cell replacement.…”