Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1

Oncogene volume 30, pages 4476–4486 (2011)Cite this article

Subjects

Abstract

A variety of cellular insults activate the tumour suppressor p53, leading generally to cell-cycle arrest or apoptosis. However, it is not inconceivable that cellular protective mechanisms may be required to keep cells alive while cell-fate decisions are made. In this respect, p53 has been suggested to perform functions that allow cells to survive, by halting of the cell-cycle, and thus preventing immediate cell death. Nonetheless, the existence of direct pro-survival p53 target genes regulating cellular survival is lacking. We show here evidence for p53-dependent cellular survival in a context-dependent manner. Both mouse and human cells lacking p53 are hypersensitive to hydrogen peroxide (H2O2)-induced cell death compared with their isogenic wild-type counterparts. By contrast, p53−/− cells are expectedly resistant to cell death upon exposure to DNA-damaging agents such as cisplatin (CDDP) and etoposide. Although p53 and its classical targets such as p21 and Mdm2 are activated by both H2O2 and CDDP, we found that the expression of haeme-oxygenase-1 (HO-1)—an antioxidant and antiapoptotic protein—was directly induced only upon H2O2 treatment in a p53-dependent manner. Consistently, p53, but not its homologue p73, activated HO-1 expression and was bound to the HO-1 promoter specifically only upon H2O2 treatment. Moreover, silencing HO-1 expression enhanced cell death upon H2O2 treatment only in p53-proficient cells. Finally, H2O2-mediated cell death was rescued significantly in p53-deficient cells by antioxidant treatment, as well as by bilirubin, a by-product of HO-1 metabolism. Taken together, these data demonstrate a direct role for p53 in promoting cellular survival in a context-specific manner through the activation of a direct transcriptional target, HO-1.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Batista LF, Roos WP, Christmann M, Menck CF, Kaina B . (2007). Differential sensitivity of malignant glioma cells to methylating and chloroethylating anticancer drugs: p53 determines the switch by regulating xpc, ddb2, and DNA double-strand breaks. Cancer Res 67: 11886–11895.

    Article  CAS  Google Scholar 

  • Brooks CL, Gu W . (2010). New insights into p53 activation. Cell Res 20: 614–621.

    Article  CAS  Google Scholar 

  • Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP . (2009). Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer 9: 862–873.

    Article  CAS  Google Scholar 

  • Burdelya LG, Komarova EA, Hill JE, Browder T, Tararova ND, Mavrakis L et al. (2006). Inhibition of p53 response in tumor stroma improves efficacy of anticancer treatment by increasing antiangiogenic effects of chemotherapy and radiotherapy in mice. Cancer Res 66: 9356–9361.

    Article  CAS  Google Scholar 

  • Buzek J, Latonen L, Kurki S, Peltonen K, Laiho M . (2002). Redox state of tumor suppressor p53 regulates its sequence-specific DNA binding in DNA-damaged cells by cysteine 277. Nucleic Acids Res 30: 2340–2348.

    Article  CAS  Google Scholar 

  • Chen-Roetling J, Benvenisti-Zarom L, Regan RF . (2005). Cultured astrocytes from heme oxygenase-1 knockout mice are more vulnerable to heme-mediated oxidative injury. J Neurosci Res 82: 802–810.

    Article  CAS  Google Scholar 

  • Choi AM, Alam J . (1996). Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 15: 9–19.

    Article  CAS  Google Scholar 

  • Fang J, Akaike T, Maeda H . (2004). Antiapoptotic role of heme oxygenase (HO) and the potential of HO as a target in anticancer treatment. Apoptosis 9: 27–35.

    Article  CAS  Google Scholar 

  • Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, Barrow RK et al. (1999). Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol 1: 152–157.

    Article  CAS  Google Scholar 

  • Foresti R, Clark JE, Green CJ, Motterlini R . (1997). Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells. Involvement of superoxide and peroxynitrite anions. J Biol Chem 272: 18411–18417.

    Article  CAS  Google Scholar 

  • Gozzelino R, Jeney V, Soares MP . (2010). Mechanisms of cell protection by heme oxygenase-1. Annu Rev Pharmacol Toxicol 50: 323–354.

    Article  CAS  Google Scholar 

  • Gudkov AV, Komarova EA . (2010). Pathologies associated with the p53 response. Cold Spring Harb Perspect Biol 2: a001180.

    Article  Google Scholar 

  • Helton ES, Chen X . (2007). p53 modulation of the DNA damage response. J Cell Biochem 100: 883–896.

    Article  CAS  Google Scholar 

  • Hermisson M, Klumpp A, Wick W, Wischhusen J, Nagel G, Roos W et al. (2006). O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells. J Neurochem 96: 766–776.

    Article  CAS  Google Scholar 

  • Hu W, Feng Z, Teresky AK, Levine AJ . (2007). p53 regulates maternal reproduction through LIF. Nature 450: 721–724.

    Article  CAS  Google Scholar 

  • Janicke RU, Sohn D, Schulze-Osthoff K . (2008). The dark side of a tumor suppressor: antiapoptotic p53. Cell Death Differ 15: 959–976.

    Article  CAS  Google Scholar 

  • Jozkowicz A, Was H, Dulak J . (2007). Heme oxygenase-1 in tumors: is it a false friend? Antioxid Redox Signal 9: 2099–2117.

    Article  CAS  Google Scholar 

  • Komarova EA, Kondratov RV, Wang K, Christov K, Golovkina TV, Goldblum JR et al. (2004). Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastrointestinal syndrome in mice. Oncogene 23: 3265–3271.

    Article  CAS  Google Scholar 

  • Lackinger D, Kaina B . (2000). Primary mouse fibroblasts deficient for c-Fos, p53 or for both proteins are hypersensitive to UV light and alkylating agent-induced chromosomal breakage and apoptosis. Mutat Res 457: 113–123.

    Article  CAS  Google Scholar 

  • Laptenko O, Prives C . (2006). Transcriptional regulation by p53: one protein, many possibilities. Cell Death Differ 13: 951–961.

    Article  CAS  Google Scholar 

  • Lassus P, Ferlin M, Piette J, Hibner U . (1996). Anti-apoptotic activity of low levels of wild-type p53. EMBO J 15: 4566–4573.

    Article  CAS  Google Scholar 

  • Lee MK, Hande MP, Sabapathy K . (2005). Ectopic mTERT expression in mouse embryonic stem cells does not affect differentiation but confers resistance to differentiation- and stress-induced p53-dependent apoptosis. J Cell Sci 118: 819–829.

    Article  CAS  Google Scholar 

  • Levine AJ, Oren M . (2009). The first 30 years of p53: growing ever more complex. Nat Rev Cancer 9: 749–758.

    Article  CAS  Google Scholar 

  • Motterlini R, Foresti R, Bassi R, Calabrese V, Clark JE, Green CJ . (2000). Endothelial heme oxygenase-1 induction by hypoxia. Modulation by inducible nitric-oxide synthase and S-nitrosothiols. J Biol Chem 275: 13613–13620.

    Article  CAS  Google Scholar 

  • Motterlini R, Green CJ, Foresti R . (2002). Regulation of heme oxygenase-1 by redox signals involving nitric oxide. Antioxid Redox Signal 4: 615–624.

    Article  CAS  Google Scholar 

  • Meiller A, Alvarez S, Drane P, Lallemand C, Blanchard B, Tovey M et al. (2007). p53-dependent stimulation of redox-related genes in the lymphoid organs of gamma-irradiated—mice identification of haeme-oxygenase 1 as a direct p53 target gene. Nucleic Acids Res 35: 6924–6934.

    Article  CAS  Google Scholar 

  • Persons DL, Yazlovitskaya EM, Pelling JC . (2000). Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin. J Biol Chem 275: 35778–35785.

    Article  CAS  Google Scholar 

  • Petrache I, Otterbein LE, Alam J, Wiegand GW, Choi AM . (2000). Heme oxygenase-1 inhibits TNF-alpha-induced apoptosis in cultured fibroblasts. Am J Physiol Lung Cell Mol Physiol 278: L312–L319.

    Article  CAS  Google Scholar 

  • Roepke M, Diestel A, Bajbouj K, Walluscheck D, Schonfeld P, Roessner A et al. (2007). Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells. Cancer Biol Ther 6: 160–169.

    Article  CAS  Google Scholar 

  • Roos WP, Batista LF, Naumann SC, Wick W, Weller M, Menck CF et al. (2007). Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene 26: 186–197.

    Article  CAS  Google Scholar 

  • Sabapathy K, Hochedlinger K, Nam SY, Bauer A, Karin M, Wagner EF . (2004). Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Mol Cell 15: 713–725.

    Article  CAS  Google Scholar 

  • Sur S, Pagliarini R, Bunz F, Rago C, Diaz Jr LA, Kinzler KW et al. (2009). A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc Natl Acad Sci USA 106: 3964–3969.

    Article  CAS  Google Scholar 

  • Vikhanskaya F, Toh WH, Dulloo I, Wu Q, Boominathan L, Ng HH et al. (2007). p73 supports cellular growth through c-Jun-dependent AP-1 transactivation. Nat Cell Biol 9: 698–705.

    Article  CAS  Google Scholar 

  • Vikhanskaya F, Vignati S, Beccaglia P, Ottoboni C, Russo P, D'Incalci M et al. (1998). Inactivation of p53 in a human ovarian cancer cell line increases the sensitivity to paclitaxel by inducing G2/M arrest and apoptosis. Exp Cell Res 241: 96–101.

    Article  CAS  Google Scholar 

  • Yu J, Zhang L, Hwang PM, Rago C, Kinzler KW, Vogelstein B . (1999). Identification and classification of p53-regulated genes. Proc Natl Acad Sci USA 96: 14517–14522.

    Article  CAS  Google Scholar 

  • Zhang Y, Lu N, Gao Z . (2009). Hemin–H2O2–NO2(−) induced protein oxidation and tyrosine nitration are different from those of SIN-1: a study on glutamate dehydrogenase nitrative/oxidative modification. Int J Biochem Cell Biol 41: 907–915.

    Article  CAS  Google Scholar 

  • Zuckerman V, Wolyniec K, Sionov RV, Haupt S, Haupt Y . (2009). Tumour suppression by p53: the importance of apoptosis and cellular senescence. J Pathol 219: 3–15.

    CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Vogelstein for the gift of the RKO cells; Ms Amy Chua HW for technical assistance during the revision phase; Dr Lee MK for critical reading of the paper and the National Medical Research Council of Singapore for the funding to KS.

Author information

Authors and Affiliations

  1. Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore

    S Y Nam & K Sabapathy

  2. Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Duke-NUS Graduate Medical School, Singapore

    K Sabapathy

  3. Department of Biochemistry,

    K Sabapathy

  4. National University of Singapore, Singapore

    K Sabapathy

Authors
  1. S Y Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Sabapathy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Sabapathy.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nam, S., Sabapathy, K. p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1. Oncogene 30, 4476–4486 (2011). https://doi.org/10.1038/onc.2011.150

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.150

Keywords

This article is cited by

Search

Advanced search

Quick links