How does p53 repress the reprogramming? p53 – the “guardian of the genome” – plays several roles in protecting the mammalian genome from genetic mutations. As a transcription factor, its activation in somatic cells by genotoxic or oncogenic stresses induces the expression of hundreds of genes, leading to cell cycle arrest, apoptosis and senescence [11
]. After oncogenic stresses, ARF plays a critical role in activating p53 [11
]. Since all reprogramming factors discovered so far have oncogenic potential, and c-Myc and Klf4 are well-established oncogenes, the ectopic expression of the reprogramming factors in somatic cells activates ARF-p53 pathways, leading to the cell cycle arrest, apoptosis and senescence of these cells, all of which could inhibit successful reprogramming (). In support of this notion, three of the five Nature
papers demonstrate that depletion of p21, the transcriptional target of p53 required for cell cycle arrest, improves the reprogramming efficiency [5
]. In addition, the other two reports indicate that oncogene-induced senescence suppresses reprogramming [8
]. It remains, however, unclear whether p53-dependent apoptosis is involved in mediating the suppression of reprogramming.
Possible mechanisms for impediment of cellular reprogramming by ARF-p53
p53 has an important role in maintaining the genetic stability of ESCs, by coordinating their DNA damage response and self-renewal [12
]. In this context, activated p53 directly suppresses the expression of Nanog, which is required for the self-renewal of ESCs, leading to the elimination of DNA damaged ESCs from the self-renewing pool. Nanog is likely to be an important factor for the self-renewal of iPSCs, the lack of p53 during reprogramming could promote the establishment and self-renewal of the newly reprogrammed iPSCs.
In the absence of p53, would the reprogrammed cells actually be useful? Reprogramming methods coupled with the inactivation or deletion of p53 enables damaged cells to be turned into iPSCs [5
]. Although the methods might not seem desirable for therapeutic use of iPSCs, they could help to establish useful cellular models for a variety of diseases in which somatic cells other than fibroblasts might need to be reprogrammed but are more difficult to reprogram. Because the persistent inactivation of p53 during reprogramming leads to apparent genomic instability and tumorigenesis of iPSCs [5
], transient p53 inactivation by small molecule inhibitors or siRNAs might be useful to reduce the trading of the cancer risk for reprogramming efficiency.
To attempt to understand the logic of genomic reprogramming, it is useful to conceptualize each cell as having reached a distinct molecular steady state through as-yet-incompletely understood genome dynamics involving gene regulation, epigenetic modifications and molecular cell physiology. Considering the critical role of p53 in suppressing reprogramming, the extremely low efficiency of reprogramming could be due to the possibility that only the cells with spontaneously mutated or epigenetically silenced ARF–p53 can be successfully reprogrammed. It would be interesting to determine whether genes involved in ARF–p53 pathways are preferentially mutated in iPSCs. Alternatively, it is possible that the action of p53 is required to prevent the generation of iPSCs containing DNA damage or DNA repair deficiency [7
]. Cells closer to pluripotency might have a lower tolerance for DNA damage, and the removal of p53 might allow these abnormalities to be passed on to reprogrammed cells. Thus, p53 could be an important regulator preventing the generation of iPSCs from damaged sources.