Abstract
BackgroundP53 is a key tumor suppressor protein. In response to DNA damage, p53 accumulates to high levels in differentiated cells and activates target genes that initiate cell cycle arrest and apoptosis. Since stem cells provide the proliferative cell pool within organisms, an efficient DNA damage response is crucial.ResultsIn proliferating embryonic stem cells, p53 is localized predominantly in the cytoplasm. DNA damage-induced nuclear accumulation of p53 in embryonic stem cells activates transcription of the target genes mdm2, p21, puma and noxa. We observed bi-phasic kinetics for nuclear accumulation of p53 after ionizing radiation. During the first wave of nuclear accumulation, p53 levels were increased and the p53 target genes mdm2, p21 and puma were transcribed. Transcription of noxa correlated with the second wave of nuclear accumulation. Transcriptional activation of p53 target genes resulted in an increased amount of proteins with the exception of p21. While p21 transcripts were efficiently translated in 3T3 cells, we failed to see an increase in p21 protein levels after IR in embryonal stem cells.ConclusionIn embryonic stem cells where (anti-proliferative) p53 activity is not necessary, or even unfavorable, p53 is retained in the cytoplasm and prevented from activating its target genes. However, if its activity is beneficial or required, p53 is allowed to accumulate in the nucleus and activates its target genes, even in embryonic stem cells.
Highlights
P53 is a key tumor suppressor protein
In embryonic stem cells where p53 activity is not necessary, or even unfavorable, p53 is retained in the cytoplasm and prevented from activating its target genes
If its activity is beneficial or required, p53 is allowed to accumulate in the nucleus and activates its target genes, even in embryonic stem cells
Summary
In response to DNA damage, p53 accumulates to high levels in differentiated cells and activates target genes that initiate cell cycle arrest and apoptosis. Cells are continuously subjected to DNA lesions arising both from environmental conditions and from the intrinsic metabolism of a cell. Such lesions can lead to mutations and large-scale genome alterations that may be deleterious for cellular function. By being part of a signal transduction process, p53 relays information leading to cellular responses such as cell cycle arrest and apoptosis, resulting from DNA lesions. In response to DNA lesions, p53 is rescued from targeted degradation, which leads to a strong increase in the amount of the otherwise shortlived tumor suppressor protein, and the protein is inten-
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