Abstract
The inactivation of p53 functions enhances the efficiency and decreases the latency of producing induced pluripotent stem cells (iPSC) in culture. The formation of iPSCs in culture starts with a rapid set of cell divisions followed by an epigenetic reprogramming of the DNA and chromatin. The mechanisms by which the p53 protein inhibits the formation of iPSCs are largely unknown. Using a temperature sensitive mutant of the p53 (Trp53) gene, we examined the impact of the temporal expression of wild type p53 in preventing stem cell induction from somatic cells. We also explored how different p53 mutant alleles affect the reprogramming process. We found that little or no p53 activity favors the entire process of somatic cell reprogramming. Reactivation of p53 at any time point during the reprogramming process not only interrupted the formation of iPSCs, but also induced newly formed stem cells to differentiate. Among p53-regulated genes, p21 (Cdkn1a), but not Puma (Bbc3) played a partial role in iPSCs formation probably by slowing cell division. Activation of p53 functions in iPSCs induced senescence and differentiation in stem cell populations. High rate of birth defects and increases in DNA methylation at the IGF2-H19 loci in female offspring of p53 knockout mice suggested that the absence of p53 may give rise to epigenetic instability in a stochastic fashion. Consistently, selected p53 missense mutations showed differential effects on the stem cell reprogramming efficiency in a c-Myc dependent manner. The absence of p53 activity and functions also contributed to an enhanced efficiency of iPSC production from cancer cells. The production of iPSCs in culture from normal and cancer cells, although different from each other in several ways, both responded to the inhibition of reprogramming by the p53 protein.
Highlights
In 2006 (1), Yamanaka and his colleagues found that a differentiated somatic cell can be dedifferentiated and reprogrammed to form a stem cell, termed an induced pluripotent stem cell, by expressing 2 embryonic stem cell (ESC)specific transcription factors Oct[4] and Sox[2] and 2 oncogenic transcription factors Klf[4] and c-Myc
ESCs, germ cells, and embryonic cancer cells all appear to have high levels of alkaline phosphatase (ALP) expression and it may be regarded as a common marker for all types of pluripotent stem cells
In the absence of p53, the ALP positive colonies were first detected around day 4 and the number kept increasing at day 6 reaching a plateau between 8 to 14 days after reprogramming began
Summary
In 2006 (1), Yamanaka and his colleagues found that a differentiated somatic cell can be dedifferentiated and reprogrammed to form a stem cell, termed an induced pluripotent stem cell (iPSC), by expressing 2 embryonic stem cell (ESC)specific transcription factors Oct[4] and Sox[2] and 2 oncogenic transcription factors Klf[4] and c-Myc. Only Oct-4 and Sox-2, or with much increased efficiencies (up to 80%) and in much shorter time frames (about 6 to 8 days in culture; 8–13) These results showed a role for p53 protein in guarding epigenetic landscapes from being reprogrammed. The reprogramming process is composed of an early rapid set of cell divisions followed by epigenetic changes of the chromatin resulting in a new pattern of transcription that reflects the pluripotent potential of stem cell for redifferentiate into one of many lineages In exploring this process, Hanna and colleagues (14) reported that the p53 protein helps control the cell-cycle acceleration, but that the increased efficiency in the formation of iPSCs cannot be explained by cell-cycle regulation through p21 alone. How the p53 protein senses the reprogramming process, what p53 does to prevent it, and when p53 functions to monitor stem cell activity remain unknown
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