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A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1.
- Source :
-
Nature [Nature] 2011 Aug 21; Vol. 477 (7364), pp. 349-53. Date of Electronic Publication: 2011 Aug 21. - Publication Year :
- 2011
-
Abstract
- The human mind and body respond to stress, 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 term. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders, and epidemiological studies strongly indicate that chronic stress leads to DNA damage. This stress-induced DNA damage may promote ageing, tumorigenesis, neuropsychiatric conditions and miscarriages. However, the mechanisms by which these DNA-damage events occur in response to stress are unknown. The stress hormone adrenaline stimulates β(2)-adrenoreceptors that are expressed throughout the body, including in germline cells and zygotic embryos. Activated β(2)-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 right. 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 β(2)-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 stress, 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.
- Subjects :
- Animals
Arrestins deficiency
Arrestins genetics
Catecholamines pharmacology
Cell Line
Cell Nucleus enzymology
Cell Nucleus metabolism
Cyclic AMP-Dependent Protein Kinases metabolism
Fibroblasts
Humans
Male
Mice
Mice, Inbred C57BL
Protein Processing, Post-Translational drug effects
Proto-Oncogene Proteins c-akt metabolism
Proto-Oncogene Proteins c-mdm2 metabolism
Signal Transduction drug effects
Testis metabolism
Thymus Gland metabolism
Tumor Suppressor Protein p53 chemistry
Tumor Suppressor Protein p53 metabolism
beta-Arrestin 1
beta-Arrestins
Arrestins metabolism
DNA Damage
Receptors, Adrenergic, beta-2 metabolism
Stress, Physiological physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 477
- Issue :
- 7364
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 21857681
- Full Text :
- https://doi.org/10.1038/nature10368