Nuclear Accumulation and Activation of P53 in Embryonic Stem Cells After DNA Damage

Overview

Journal BMC Cell Biol

Publisher Biomed Central

Specialty Cell Biology

Date 2009 Jun 19

PMID 19534768

Citations 58

Authors

Valeriya Solozobova

Alexandra Rolletschek

Christine Blattner

Affiliations

Soon will be listed here.

Abstract

Background: P53 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.

Results: In 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.

Conclusion: In 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.

Citing Articles

DNA-damage orchestrates self-renewal and differentiation via reciprocal p53 family and Hippo/Wnt/TGF-β pathway activation in embryonic stem cells.

Ye Y, Xie W, Wang X, Tan S, Yang L, Ma Z Cell Mol Life Sci. 2025; 82(1):38.

PMID: 39762370 PMC: 11704118. DOI: 10.1007/s00018-024-05561-0.

Transcriptome Analysis by RNA Sequencing of Mouse Embryonic Stem Cells Stocked on International Space Station for 1584 Days in Frozen State after Culture on the Ground.

Yoshida K, Hada M, Hayashi M, Kizu A, Kitada K, Eguchi-Kasai K Int J Mol Sci. 2024; 25(6).

PMID: 38542258 PMC: 10970647. DOI: 10.3390/ijms25063283.

Senescent Secretome of Blind Mole Rat Inhibits Malignant Behavior of Human Breast Cancer Cells Triggering Bystander Senescence and Targeting Inflammatory Response.

Odeh A, Eddini H, Shawasha L, Chaban A, Avivi A, Shams I Int J Mol Sci. 2023; 24(6).

PMID: 36982207 PMC: 10049022. DOI: 10.3390/ijms24065132.

Eltanexor Effectively Reduces Viability of Glioblastoma and Glioblastoma Stem-Like Cells at Nano-Molar Concentrations and Sensitizes to Radiotherapy and Temozolomide.

Otte K, Zhao K, Braun M, Neubauer A, Raifer H, Helmprobst F Biomedicines. 2022; 10(9).

PMID: 36140245 PMC: 9496210. DOI: 10.3390/biomedicines10092145.

A Single-Cell Raman Spectroscopy Analysis of Bone Marrow Mesenchymal Stem/Stromal Cells to Identify Inter-Individual Diversity.

Kukolj T, Lazarevic J, Borojevic A, Ralevic U, Vujic D, Jaukovic A Int J Mol Sci. 2022; 23(9).

PMID: 35563306 PMC: 9103070. DOI: 10.3390/ijms23094915.

References

Chan W, Poon R . The p53 Isoform Deltap53 lacks intrinsic transcriptional activity and reveals the critical role of nuclear import in dominant-negative activity. Cancer Res. 2007; 67(5):1959-69. DOI: 10.1158/0008-5472.CAN-06-3602. View

Symonds H, Krall L, Remington L, Lowe S, Jacks T, Van Dyke T . p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell. 1994; 78(4):703-11. DOI: 10.1016/0092-8674(94)90534-7. View

Vousden K . Outcomes of p53 activation--spoilt for choice. J Cell Sci. 2006; 119(Pt 24):5015-20. DOI: 10.1242/jcs.03293. View

Lane D . Cancer. p53, guardian of the genome. Nature. 1992; 358(6381):15-6. DOI: 10.1038/358015a0. View

Yin Y, Tainsky M, Bischoff F, Strong L, Wahl G . Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell. 1992; 70(6):937-48. DOI: 10.1016/0092-8674(92)90244-7. View

El-Deiry W, Tokino T, Velculescu V, Levy D, Parsons R, Trent J . WAF1, a potential mediator of p53 tumor suppression. Cell. 1993; 75(4):817-25. DOI: 10.1016/0092-8674(93)90500-p. View

Nakano K, Vousden K . PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell. 2001; 7(3):683-94. DOI: 10.1016/s1097-2765(01)00214-3. View

Barak Y, Juven T, Haffner R, Oren M . mdm2 expression is induced by wild type p53 activity. EMBO J. 1993; 12(2):461-8. PMC: 413229. DOI: 10.1002/j.1460-2075.1993.tb05678.x. View

Martin L, Liu Z, Pipino J, Chestnut B, Landek M . Molecular regulation of DNA damage-induced apoptosis in neurons of cerebral cortex. Cereb Cortex. 2008; 19(6):1273-93. PMC: 2677647. DOI: 10.1093/cercor/bhn167. View

10.

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

11.

Clarke A, Gledhill S, Hooper M, Bird C, Wyllie A . p53 dependence of early apoptotic and proliferative responses within the mouse intestinal epithelium following gamma-irradiation. Oncogene. 1994; 9(6):1767-73. View

12.

Blattner C, Tobiasch E, Litfen M, Rahmsdorf H, Herrlich P . DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation. Oncogene. 1999; 18(9):1723-32. DOI: 10.1038/sj.onc.1202480. View

13.

Donehower L, Harvey M, Slagle B, McArthur M, Montgomery Jr C, Butel J . Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992; 356(6366):215-21. DOI: 10.1038/356215a0. View

14.

Cervantes R, Stringer J, Shao C, Tischfield J, Stambrook P . Embryonic stem cells and somatic cells differ in mutation frequency and type. Proc Natl Acad Sci U S A. 2002; 99(6):3586-90. PMC: 122567. DOI: 10.1073/pnas.062527199. View

15.

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

16.

Kastan M, Onyekwere O, Sidransky D, Vogelstein B, Craig R . Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991; 51(23 Pt 1):6304-11. View

17.

Waard H, de Wit J, Gorgels T, van den Aardweg G, Andressoo J, Vermeij M . Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice. DNA Repair (Amst). 2003; 2(1):13-25. DOI: 10.1016/s1568-7864(02)00188-x. View

18.

Blattner C . Regulation of p53: the next generation. Cell Cycle. 2008; 7(20):3149-53. DOI: 10.4161/cc.7.20.6921. View

19.

Harvey M, McArthur M, Montgomery Jr C, Butel J, Bradley A, Donehower L . Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat Genet. 1993; 5(3):225-9. DOI: 10.1038/ng1193-225. View

20.

Blattner C, Hay T, Meek D, Lane D . Hypophosphorylation of Mdm2 augments p53 stability. Mol Cell Biol. 2002; 22(17):6170-82. PMC: 134018. DOI: 10.1128/MCB.22.17.6170-6182.2002. View