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.

A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1

Nature volume 477, pages 349–353 (2011)Cite this article

Subjects

Abstract

The human mind and body respond to stress1, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the ‘fight-or-flight’ response. The stress response is generally transient because its accompanying effects (for example, immunosuppression, growth inhibition and enhanced catabolism) can be harmful in the long term2. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders3, and epidemiological studies strongly indicate that chronic stress leads to DNA damage4,5. This stress-induced DNA damage may promote ageing6, tumorigenesis4,7, neuropsychiatric conditions8,9 and miscarriages10. However, the mechanisms by which these DNA-damage events occur in response to stress are unknown. The stress hormone adrenaline stimulates β2-adrenoreceptors that are expressed throughout the body, including in germline cells and zygotic embryos11. Activated β2-adrenoreceptors promote Gs-protein-dependent activation of protein kinase A (PKA), followed by the recruitment of β-arrestins, which desensitize G-protein signalling and function as signal transducers in their own right12. Here we elucidate a molecular mechanism by which β-adrenergic catecholamines, acting through both Gs–PKA and β-arrestin-mediated signalling pathways, trigger DNA damage and suppress p53 levels respectively, thus synergistically leading to the accumulation of DNA damage. In mice and in human cell lines, β-arrestin-1 (ARRB1), activated via β2-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. Catecholamine-induced DNA damage is abrogated in Arrb1-knockout (Arrb1−/−) mice, which show preserved p53 levels in both the thymus, an organ that responds prominently to acute or chronic stress1, and in the testes, in which paternal stress may affect the offspring’s genome. Our results highlight the emerging role of ARRB1 as an E3-ligase adaptor in the nucleus, and reveal how DNA damage may accumulate in response to chronic stress.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Chronic catecholamine stimulation leads to p53 degradation and accumulation of DNA damage via ARRB1/AKT-mediated activation of MDM2.
Figure 2: ARRB1 functions as an E3 ligase adaptor for MDM2 and p53 upon catecholamine stimulation.
Figure 3: ARRB1 facilitates catecholamine-induced p53 degradation by MDM2.
Figure 4: Chronic catecholamine stimulation leads to accumulation of DNA damage by an ARRB1- and p53-dependent mechanism.

References

  1. Selye, H. A syndrome produced by diverse nocuous agents. Nature 138, 32 (1936)

    Article  ADS  Google Scholar 

  2. Charmandari, E., Tsigos, C. & Chrousos, G. Endocrinology of the stress response. Annu. Rev. Physiol. 67, 259–284 (2005)

    Article  CAS  Google Scholar 

  3. Goldstein, D. S. Catecholamines and stress. Endocr. Regul. 37, 69–80 (2003)

    CAS  PubMed  Google Scholar 

  4. Antoni, M. H. et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Natl. Rev. 6, 240–248 (2006)

    Article  CAS  Google Scholar 

  5. Flint, M. S., Baum, A., Chambers, W. H. & Jenkins, F. J. Induction of DNA damage, alteration of DNA repair and transcriptional activation by stress hormones. Psychoneuroendocrinology 32, 470–479 (2007)

    Article  CAS  Google Scholar 

  6. Lu, T. et al. Gene regulation and DNA damage in the ageing human brain. Nature 429, 883–891 (2004)

    Article  ADS  CAS  Google Scholar 

  7. Thaker, P. H. et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nature Med. 12, 939–944 (2006)

    Article  CAS  Google Scholar 

  8. Fratiglioni, L., Paillard-Borg, S. & Winblad, B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol. 3, 343–353 (2004)

    Article  Google Scholar 

  9. Kinney, D. K., Munir, K. M., Crowley, D. J. & Miller, A. M. Prenatal stress and risk for autism. Neurosci. Biobehav. Rev. 32, 1519–1532 (2008)

    Article  Google Scholar 

  10. Nepomnaschy, P. A. et al. Cortisol levels and very early pregnancy loss in humans. Proc. Natl Acad. Sci. USA 103, 3938–3942 (2006)

    Article  ADS  CAS  Google Scholar 

  11. Cˇikosˇ, S. et al. Expression of beta adrenergic receptors in mouse oocytes and preimplantation embryos. Mol. Reprod. Dev. 71, 145–153 (2005)

    Article  Google Scholar 

  12. DeWire, S. M., Ahn, S., Lefkowitz, R. J. & Shenoy, S. K. β-arrestins and cell signaling. Annu. Rev. Physiol. 69, 483–510 (2007)

    Article  CAS  Google Scholar 

  13. Ni, Y. et al. Activation of β2-adrenergic receptor stimulates γ-secretase activity and accelerates amyloid plaque formation. Nature Med. 12, 1390–1396 (2006)

    Article  CAS  Google Scholar 

  14. Bonner, W. M. et al. GammaH2AX and cancer. Nature Rev. Cancer 8, 957–67 (2008)

    Article  CAS  Google Scholar 

  15. Freedman, D. A. & Levine, A. J. Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol. Cell. Biol. 18, 7288–7293 (1998)

    Article  CAS  Google Scholar 

  16. Rainbow, T. C., Parsons, B. & Wolfe, B. B. Quantitative autoradiography of beta 1- and beta 2-adrenergic receptors in rat brain. Proc. Natl Acad. Sci. USA 81, 1585–1589 (1984)

    Article  ADS  CAS  Google Scholar 

  17. Zhou, B. P. et al. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nature Cell Biol. 3, 973–982 (2001)

    Article  CAS  Google Scholar 

  18. De Gregorio, G. et al. The p85 regulatory subunit of PI3K mediates TSH–cAMP–PKA growth and survival signals. Oncogene 26, 2039–2047 (2007)

    Article  CAS  Google Scholar 

  19. Goel, R., Phillips-Mason, P. J., Raben, D. M. & Baldassare, J. J. α-Thrombin induces rapid and sustained Akt phosphorylation by β-arrestin1-dependent and -independent mechanisms, and only the sustained Akt phosphorylation is essential for G1 phase progression. J. Biol. Chem. 277, 18640–18648 (2002)

    Article  CAS  Google Scholar 

  20. Buchanan, F. G. et al. Role of β-arrestin 1 in the metastatic progression of colorectal cancer. Proc. Natl Acad. Sci. USA 103, 1492–1497 (2006)

    Article  ADS  CAS  Google Scholar 

  21. Kovacs, J. J., Hara, M. R., Davenport, C. L., Kim, J. & Lefkowitz, R. J. Arrestin development: emerging roles for β-arrestins in developmental signaling pathways. Dev. Cell 17, 443–458 (2009)

    Article  CAS  Google Scholar 

  22. Scott, M. G. et al. Differential nucleocytoplasmic shuttling of β-arrestins. Characterization of a leucine-rich nuclear export signal in β-arrestin2. J. Biol. Chem. 277, 37693–37701 (2002)

    Article  CAS  Google Scholar 

  23. Wang, P., Wu, Y., Ge, X., Ma, L. & Pei, G. Subcellular localization of β-arrestins is determined by their intact N domain and the nuclear export signal at the C terminus. J. Biol. Chem. 278, 11648–11653 (2003)

    Article  CAS  Google Scholar 

  24. Wang, P. et al. β-arrestin 2 functions as a G-protein-coupled receptor-activated regulator of oncoprotein Mdm2. J. Biol. Chem. 278, 6363–6370 (2003)

    Article  CAS  Google Scholar 

  25. Boularan, C. et al. β-arrestin 2 oligomerization controls the Mdm2-dependent inhibition of p53. Proc. Natl Acad. Sci. USA 104, 18061–18066 (2007)

    Article  ADS  CAS  Google Scholar 

  26. Nobles, K. N., Guan, Z., Xiao, K., Oas, T. G. & Lefkowitz, R. J. The active conformation of β-arrestin1: direct evidence for the phosphate sensor in the N-domain and conformational differences in the active states of β-arrestins1 and -2. J. Biol. Chem. 282, 21370–21381 (2007)

    Article  CAS  Google Scholar 

  27. Yan, L. et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130, 247–258 (2007)

    Article  CAS  Google Scholar 

  28. Sengupta, S. & Harris, C. C. p53: traffic cop at the crossroads of DNA repair and recombination. Nature Rev. Mol. Cell Biol. 6, 44–55 (2005)

    Article  CAS  Google Scholar 

  29. Schuller, H. M. Mechanisms of smoking-related lung and pancreatic adenocarcinoma development. Nature Rev. Cancer 2, 455–463 (2002)

    Article  CAS  Google Scholar 

  30. Khachaturian, A. S. et al. Antihypertensive medication use and incident Alzheimer disease: the Cache County Study. Arch. Neurol. 63, 686–692 (2006)

    Article  Google Scholar 

  31. Attramadal, H. et al. β-arrestin2, a novel member of the arrestin/β-arrestin gene family. J. Biol. Chem. 267, 17882–17890 (1992)

    CAS  PubMed  Google Scholar 

  32. Xiao, K., Shenoy, S. K., Nobles, K. & Lefkowitz, R. J. Activation-dependent conformational changes in β-arrestin 2. J. Biol. Chem. 279, 55744–55753 (2004)

    Article  CAS  Google Scholar 

  33. Koldobskiy, M. A. et al. p53-mediated apoptosis requires inositol hexakisphosphate kinase-2. Proc. Natl Acad. Sci. USA 107, 20947–20951 (2010)

    Article  ADS  CAS  Google Scholar 

  34. Hara, M. R. et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nature Cell Biol. 7, 665–674 (2005)

    Article  CAS  Google Scholar 

  35. Kohout, T. A., Lin, F. S., Perry, S. J., Conner, D. A. & Lefkowitz, R. J. β-Arrestin 1 and 2 differentially regulate heptahelical receptor signaling and trafficking. Proc. Natl Acad. Sci. USA 98, 1601–1606 (2001)

    ADS  CAS  PubMed  Google Scholar 

  36. Todaro, G. J. & Green, H. Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J. Cell Biol. 17, 299–313 (1963)

    Article  CAS  Google Scholar 

  37. Brummelkamp, T. R., Bernards, R. & Agami, R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002)

    Article  ADS  CAS  Google Scholar 

  38. Yu, J. Y., DeRuiter, S. L. & Turner, D. L. RNA interference by expression of short-interfering RNAs and hairpin RNAs in mammalian cells. Proc. Natl Acad. Sci. USA 99, 6047–6052 (2002)

    Article  ADS  CAS  Google Scholar 

  39. Seshadri, T. & Campisi, J. Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science 247, 205–209 (1990)

    Article  ADS  CAS  Google Scholar 

  40. Conner, D. A. et al. β-Arrestin1 knockout mice appear normal but demonstrate altered cardiac responses to β-adrenergic stimulation. Circ. Res. 81, 1021–1026 (1997)

    Article  CAS  Google Scholar 

  41. Chruscinski, A. J. et al. Targeted disruption of the β2 adrenergic receptor gene. J. Biol. Chem. 274, 16694–16700 (1999)

    Article  CAS  Google Scholar 

  42. Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25, 402–408 (2001)

    Article  CAS  Google Scholar 

  43. Kovacs, J. J. et al. β-arrestin-mediated localization of smoothened to the primary cilium. Science 320, 1777–1781 (2008)

    Article  ADS  CAS  Google Scholar 

  44. Lista, F., Bertness, V., Guidos, C. J., Danska, J. S. & Kirsch, I. R. The absolute number of trans-rearrangements between the TCRG and TCRB loci is predictive of lymphoma risk: a severe combined immune deficiency (SCID) murine model. Cancer Res. 57, 4408–4413 (1997)

    CAS  PubMed  Google Scholar 

  45. Olshen, A. B., Venkatraman, E. S., Lucito, R. & Wigler, M. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5, 557–572 (2004)

    Article  Google Scholar 

  46. Hausdorff, W. P., Hnatowich, M., O’Dowd, B. F., Caron, M. G. & Lefkowitz, R. J. A mutation of the β 2-adrenergic receptor impairs agonist activation of adenylyl cyclase without affecting high affinity agonist binding. Distinct molecular determinants of the receptor are involved in physical coupling to and functional activation of Gs. J. Biol. Chem. 265, 1388–1393 (1990)

    CAS  PubMed  Google Scholar 

  47. Baker, J. G. The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors. Br. J. Pharmacol. 144, 317–322 (2005)

    Article  CAS  Google Scholar 

  48. Cheng, Y. & Prusoff, W. H. Relationship between the inhibition constant (K I) and the concentration of inhibitor which causes 50 per cent inhibition (I 50) of an enzymatic reaction. Biochem. Pharmacol. 22, 3099–3108 (1973)

    Article  CAS  Google Scholar 

  49. Nowak, D. E., Tian, B. & Brasier, A. R. Two-step cross-linking method for identification of NF-κB gene network by chromatin immunoprecipitation. Biotechniques 39, 715–725 (2005)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

R.J.L. is a Howard Hughes Medical Institute investigator. This work was supported by HL16037 and HL70631 (R.J.L.). We thank D. Addison and Q. Lennon for secretarial assistance; S. H. Snyder and M. A. Koldobskiy for providing p53 deletion constructs; B. K. Kobilka and H. A. Rockman for providing Adrb2−/− mice; M. C. Hung for providing the MDM2-S166D plasmid; A. K. Shukla, A. Kahsai, J. Kim, J. Sun, S. M. DeWire and N. Odajima for discussion and comments.

Author information

Authors and Affiliations

  1. Department of Medicine, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Makoto R. Hara, Jeffrey J. Kovacs, Erin J. Whalen, Sudarshan Rajagopal, Ryan T. Strachan, Aaron J. Towers, Barbara Williams, Christopher M. Lam, Kunhong Xiao, Sudha K. Shenoy, Simon G. Gregory, Seungkirl Ahn & Robert J. Lefkowitz

  2. Translational Research Institute, The Scripps Research Institute, Jupiter, 33458, Florida, USA

    Wayne Grant & Derek R. Duckett

  3. Center for Human Genetics, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Aaron J. Towers & Simon G. Gregory

  4. Howard Hughes Medical Institute, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Robert J. Lefkowitz

Authors
  1. Makoto R. Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey J. Kovacs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erin J. Whalen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sudarshan Rajagopal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryan T. Strachan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wayne Grant
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aaron J. Towers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Barbara Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christopher M. Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kunhong Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sudha K. Shenoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Simon G. Gregory
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Seungkirl Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Derek R. Duckett
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Robert J. Lefkowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.R.H. and R.J.L. designed experiments, directed the study and wrote the paper. M.R.H. performed most of the experiments, analysed the data and prepared the figures. R.J.L. supervised the study and provided financial support. J.J.K. performed some experiments, helped to analyse the data and helped to write the paper. E.J.W., S.R., K.X., S.K.S. and S.A. helped to analyse the data. E.J.W., S.R., R.T.S., B.W., C.M.L. and S.A. performed some experiments. A.J.T. and S.G.G. performed the array-CGH and helped to analyse the data. W.G. and D.R.D. helped to characterize the functionality of p53 and to analyse the data.

Corresponding author

Correspondence to Robert J. Lefkowitz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-6 with legends. (PDF 2462 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hara, M., Kovacs, J., Whalen, E. et al. A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1. Nature 477, 349–353 (2011). https://doi.org/10.1038/nature10368

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10368

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing