Abstract
cIAP1 is an important member of the inhibitor of apoptosis family of proteins and is involved in the regulation of the NF-κB-signalling pathway downstream of the TNF receptor. We report here that UV irradiation leads to downregulation of cIAP1 expression because of enhanced cIAP1 mRNA destabilization. An AU-rich element located within the 3′ untranslated region of cIAP1 mRNA is sufficient to mediate cIAP1 mRNA instability. Furthermore, we have identified hnRNP A1 as a cIAP1 3′UTR-binding protein. hnRNP A1 is a primarily nuclear protein, but accumulates in the cytoplasm after exposure of cells to UV irradiation. Indeed, we find that hnRNP A1 enhances the destabilization of cIAP1 mRNA during UV irradiation. Moreover, siRNA-mediated knockdown of hnRNP A1 restores cIAP1 levels and prevents UV irradiation-induced activation of the NF-κB signal transduction pathway, suggesting that hnRNP A1 is an essential post-transcriptional modulator of cIAP1 expression, and thus cIAP1 activity.
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Abbreviations
- ARE:
-
AU-rich element
- CAT:
-
chloramphenicol acetyl transferase
- hnRNP A1:
-
heterogeneous ribonucleoprotein A1
- IAP:
-
inhibitor of apoptosis
- IRES:
-
internal ribosome entry site
- NEO:
-
neomycin phosphotransferase
- NF-κB:
-
nuclear factor kappa B
- RING:
-
really interesting new gene
- TNFα:
-
tumour necrosis factor α
- UTR:
-
untranslated region
- UVR:
-
UV irradiation
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Acknowledgements
This work was supported by a discovery grant from the National Sciences and Engineering Research Council of Canada (NSERC). J.C. is the recipient of Canada Research Chair (Tier 2) in RNA Metabolism. I.G. is supported by a scholarship from Fonds pour la Recherche en Santé du Québec (FRSQ). T.E.G. is supported by the Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award. M.H. is the CHEO Volunteer Association Endowed Scholar
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Zhao, T., Graber, T., Jordan, L. et al. hnRNP A1 regulates UV-induced NF-κB signalling through destabilization of cIAP1 mRNA. Cell Death Differ 16, 244–252 (2009). https://doi.org/10.1038/cdd.2008.146
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DOI: https://doi.org/10.1038/cdd.2008.146
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