SIRT1 Regulates Apoptosis and Nanog Expression in Mouse Embryonic Stem Cells by Controlling P53 Subcellular Localization

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2008 Mar 29

PMID 18371449

Citations 201

Authors

Myung-Kwan Han

Eun-Kyung Song

Ying Guo

Xuan Ou

Charlie Mantel

Hal E Broxmeyer

Affiliations

Soon will be listed here.

Abstract

Nuclear tumor suppressor p53 transactivates proapoptotic genes or antioxidant genes depending on stress severity, while cytoplasmic p53 induces mitochondrial-dependent apoptosis without gene transactivation. Although SIRT1, a p53 deacetylase, inhibits p53-mediated transactivation, how SIRT1 regulates these p53 multifunctions is unclear. Here we show that SIRT1 blocks nuclear translocation of cytoplasmic p53 in response to endogenous reactive oxygen species (ROS) and triggers mitochondrial-dependent apoptosis in mouse embryonic stem (mES) cells. ROS generated by antioxidant-free culture caused p53 translocation into mitochondria in wild-type mES cells but induced p53 translocation into the nucleus in SIRT1(-/-) mES cells. Endogenous ROS triggered apoptosis of wild-type mES through mitochondrial translocation of p53 and BAX but inhibited Nanog expression of SIRT1(-/-) mES, indicating that SIRT1 makes mES cells sensitive to ROS and inhibits p53-mediated suppression of Nanog expression. Our results suggest that endogenous ROS control is important for mES cell maintenance in culture.

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References

Huang C, Ma W, Goranson A, Dong Z . Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathway. Carcinogenesis. 1999; 20(2):237-42. DOI: 10.1093/carcin/20.2.237. View

Wang Y, Prives C . Increased and altered DNA binding of human p53 by S and G2/M but not G1 cyclin-dependent kinases. Nature. 1995; 376(6535):88-91. DOI: 10.1038/376088a0. View

Macip S, Igarashi M, Berggren P, Yu J, Lee S, Aaronson S . Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol Cell Biol. 2003; 23(23):8576-85. PMC: 262651. DOI: 10.1128/MCB.23.23.8576-8585.2003. View

Luo J, Nikolaev A, Imai S, Chen D, Su F, SHILOH A . Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001; 107(2):137-48. DOI: 10.1016/s0092-8674(01)00524-4. View

Kume S, Haneda M, Kanasaki K, Sugimoto T, Araki S, Isono M . Silent information regulator 2 (SIRT1) attenuates oxidative stress-induced mesangial cell apoptosis via p53 deacetylation. Free Radic Biol Med. 2006; 40(12):2175-82. DOI: 10.1016/j.freeradbiomed.2006.02.014. View

Solomon J, Pasupuleti R, Xu L, McDonagh T, Curtis R, DiStefano P . Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol Cell Biol. 2005; 26(1):28-38. PMC: 1317617. DOI: 10.1128/MCB.26.1.28-38.2006. View

Kamel C, Abrol M, Jardine K, He X, McBurney M . SirT1 fails to affect p53-mediated biological functions. Aging Cell. 2006; 5(1):81-8. DOI: 10.1111/j.1474-9726.2006.00191.x. View

Miyashita T, Reed J . Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995; 80(2):293-9. DOI: 10.1016/0092-8674(95)90412-3. View

Sawai S, Shimono A, Hanaoka K, Kondoh H . Embryonic lethality resulting from disruption of both N-myc alleles in mouse zygotes. New Biol. 1991; 3(9):861-9. View

10.

Lin T, Chao C, Saito S, Mazur S, Murphy M, Appella E . p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol. 2004; 7(2):165-71. DOI: 10.1038/ncb1211. View

11.

Aladjem M, Spike B, Rodewald L, Hope T, Klemm M, Jaenisch R . ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage. Curr Biol. 1998; 8(3):145-55. DOI: 10.1016/s0960-9822(98)70061-2. View

12.

Hupp T, Meek D, Midgley C, Lane D . Regulation of the specific DNA binding function of p53. Cell. 1992; 71(5):875-86. DOI: 10.1016/0092-8674(92)90562-q. View

13.

Ezashi T, Das P, Roberts R . Low O2 tensions and the prevention of differentiation of hES cells. Proc Natl Acad Sci U S A. 2005; 102(13):4783-8. PMC: 554750. DOI: 10.1073/pnas.0501283102. View

14.

Rodriguez M, Desterro J, Lain S, Midgley C, Lane D, Hay R . SUMO-1 modification activates the transcriptional response of p53. EMBO J. 1999; 18(22):6455-61. PMC: 1171708. DOI: 10.1093/emboj/18.22.6455. View

15.

Bordone L, Guarente L . Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol. 2005; 6(4):298-305. DOI: 10.1038/nrm1616. View

16.

Pluquet O, Hainaut P . Genotoxic and non-genotoxic pathways of p53 induction. Cancer Lett. 2001; 174(1):1-15. DOI: 10.1016/s0304-3835(01)00698-x. View

17.

Budanov A, Sablina A, Feinstein E, Koonin E, Chumakov P . Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science. 2004; 304(5670):596-600. DOI: 10.1126/science.1095569. View

18.

Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P . p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003; 11(3):577-90. DOI: 10.1016/s1097-2765(03)00050-9. View

19.

Khosravi R, Maya R, Gottlieb T, Oren M, Shiloh Y, Shkedy D . Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc Natl Acad Sci U S A. 1999; 96(26):14973-7. PMC: 24757. DOI: 10.1073/pnas.96.26.14973. View

20.

Werner E . Determination of cellular H2O2 production. Sci STKE. 2003; 2003(168):PL3. DOI: 10.1126/stke.2003.168.pl3. View