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Puma is required for p53-induced depletion of adult stem cells

Nature Cell Biology volume 12, pages 993–998 (2010)Cite this article

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Abstract

Mammalian ageing is accompanied by accumulation of genomic DNA damage and progressive decline in the ability of tissues to regenerate1. DNA damage activates the tumour suppressor p53, which leads to cell-cycle arrest, senescence or apoptosis. The stability and activity of p53 are induced by DNA damage through posttranslational modifications such as phosphorylation of Thr 21 and Ser 23 (refs 2, 3, 4, 5). To investigate the roles of DNA damage and p53 in tissue-regenerative capability, two phosphorylation-site mutations (T21D and S23D) were introduced into the endogenous p53 gene in mice, so that the synthesized protein mimics phosphorylated p53. The knock-in mice exhibit constitutive p53 activation and segmental progeria that is correlated with the depletion of adult stem cells in multiple tissues, including bone marrow, brain and testes. Furthermore, a deficiency of Puma, which is required for p53-dependent apoptosis after DNA damage6, rescues segmental progeria and prevents the depletion of adult stem cells. These findings suggest a key role of p53-dependent apoptosis in depleting adult stem cells after the accumulation of DNA damage, which leads to a decrease in tissue regeneration.

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Figure 1: p53TSD/− mice exhibit segmental progeria and constitutively active p53.
Figure 2: Progressive degeneration of the haematopoietic system in p53TSD/− mice.
Figure 3: Depletion of adult neural stem cells in the dentate gyrus of p53TSD/− mice, which is suppressed by Puma-deficiency.
Figure 4: Testicular atrophy and depletion of SSCs in p53TSD/− mice.
Figure 5: Puma-deficiency rescues the segmental progeria phenotypes and inhibits the depletion of adult stem cells in p53TSD/− mice.

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Acknowledgements

We thank H. Tian and O. Gaidarenko for technical support, and N. Varki for help with mouse pathology. This work is supported by a National Institutes of Health (NIH) grant to Y.X. (CA094254).

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Authors and Affiliations

  1. Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0322, CA, USA

    Dongping Liu, Linda Ou, Connie Chao, Marshall Eli Lutske & Yang Xu

  2. Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Gregory D. Clemenson Jr & Fred H. Gage

  3. Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, 38105, TN, USA

    Gerard P. Zambetti

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  1. Dongping Liu
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Contributions

D.P.L. and Y.X. designed and conducted experiments, and wrote the manuscript. L.O., C.C. and M.E.L. carried out experiments including the rescue experiments by p21-deficiency and Puma-deficiency. G.D.C. Jr. and F.H.G analysed the neural stem cells and revised the manuscript. G.P.Z. provided the Puma−/− mice, consulted on the experiments and was involved in writing of the manuscript.

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Correspondence to Yang Xu.

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Liu, D., Ou, L., Clemenson, G. et al. Puma is required for p53-induced depletion of adult stem cells. Nat Cell Biol 12, 993–998 (2010). https://doi.org/10.1038/ncb2100

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