Aryl Hydrocarbon Receptor-Dependent Retention of Nuclear HuR Suppresses Cigarette Smoke-Induced Cyclooxygenase-2 Expression Independent of DNA-Binding

Michela Zago, Jared A. Sheridan, Parameswaran Nair, Angela Rico de Souza, Imed Gallouzi, Simon Rousseau, Sergio Di Marco, Qutayba Hamid, David H. Eidelman, Carolyn J. Baglole

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that responds to man-made environmental toxicants, has emerged as an endogenous regulator of cyclooxygenase-2 (Cox-2) by a mechanism that is poorly understood. In this study, we first used AhR-deficient (AhR-/-) primary pulmonary cells, together with pharmacological tools to inhibit new RNA synthesis, to show that the AhR is a prominent factor in the destabilization of Cox-2 mRNA. The destabilization of Cox-2 mRNA and subsequent suppression of cigarette smoke-induced COX-2 protein expression by the AhR was independent of its ability to bind the dioxin response element (DRE), thereby differentiating the DRE-driven toxicological AhR pathway from its anti-inflammatory abilities. We further describe that the AhR destabilizes Cox-2 mRNA by sequestering HuR within the nucleus. The role of HuR in AhR stabilization of Cox-2 mRNA was confirmed by knockdown of HuR, which resulted in rapid Cox-2 mRNA degradation. Finally, in the lungs of AhR-/- mice exposed to cigarette smoke, there was little Cox-2 mRNA despite robust COX-2 protein expression, a finding that correlates with almost exclusive cytoplasmic HuR within the lungs of AhR-/- mice. Therefore, we propose that the AhR plays an important role in suppressing the expression of inflammatory proteins, a function that extends beyond the ability of the AhR to respond to man-made toxicants. These findings open the possibility that a DRE-independent AhR pathway may be exploited therapeutically as an anti-inflammatory target.

Original languageEnglish
Article numbere74953
JournalPLoS One
Volume8
Issue number9
DOIs
Publication statusPublished - 27 Sep 2013
Externally publishedYes

Fingerprint

Aryl Hydrocarbon Receptors
cigarettes
prostaglandin synthase
Cyclooxygenase 2
smoke
Smoke
Tobacco Products
hydrocarbons
receptors
DNA
Messenger RNA
Dioxins
Response Elements
dioxins
response elements
Lung
lungs
toxic substances
Anti-Inflammatory Agents
protein synthesis

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Aryl Hydrocarbon Receptor-Dependent Retention of Nuclear HuR Suppresses Cigarette Smoke-Induced Cyclooxygenase-2 Expression Independent of DNA-Binding. / Zago, Michela; Sheridan, Jared A.; Nair, Parameswaran; Rico de Souza, Angela; Gallouzi, Imed; Rousseau, Simon; Di Marco, Sergio; Hamid, Qutayba; Eidelman, David H.; Baglole, Carolyn J.

In: PLoS One, Vol. 8, No. 9, e74953, 27.09.2013.

Research output: Contribution to journalArticle

Zago, M, Sheridan, JA, Nair, P, Rico de Souza, A, Gallouzi, I, Rousseau, S, Di Marco, S, Hamid, Q, Eidelman, DH & Baglole, CJ 2013, 'Aryl Hydrocarbon Receptor-Dependent Retention of Nuclear HuR Suppresses Cigarette Smoke-Induced Cyclooxygenase-2 Expression Independent of DNA-Binding', PLoS One, vol. 8, no. 9, e74953. https://doi.org/10.1371/journal.pone.0074953
Zago, Michela ; Sheridan, Jared A. ; Nair, Parameswaran ; Rico de Souza, Angela ; Gallouzi, Imed ; Rousseau, Simon ; Di Marco, Sergio ; Hamid, Qutayba ; Eidelman, David H. ; Baglole, Carolyn J. / Aryl Hydrocarbon Receptor-Dependent Retention of Nuclear HuR Suppresses Cigarette Smoke-Induced Cyclooxygenase-2 Expression Independent of DNA-Binding. In: PLoS One. 2013 ; Vol. 8, No. 9.
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