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Glucocorticoid receptor interacting protein-1 restores glococorticoid responsiveness in steroid-resistant airway structural cells

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journal contribution
posted on 25.06.2010, 09:50 by Reena Bhandare, Gautam Damera, Audreesh Banerjee, Jamie R. Flammer, Stefan Keslacy, Inez Rogatsky, Reynold A. Panettieri, Yassine Amrani, Omar Tliba
Glucocorticoid (GC) insensitivity represents a profound challenge in managing patients with asthma. The mutual inhibition of transcriptional activity between GC receptor (GR) and other regulators is one of the mechanisms contributing to GC resistance in asthma. We recently reported that interferon regulatory factor (IRF)-1 is a novel transcription factor that promotes GC insensitivity in human airway smooth muscle (ASM) cells by interfering with GR signaling (Tliba et al., Am J Respir Cell Mol Biol 2008;38:463–472). Here, we sought to determine whether the inhibition of GR function by IRF-1 involves its interaction with the transcriptional co-regulator GR-interacting protein 1 (GRIP-1), a known GR transcriptional co-activator. We here found that siRNA-mediated GRIP-1 depletion attenuated IRF-1–dependent transcription of the luciferase reporter construct and the mRNA expression of an IRF-1–dependent gene, CD38. In parallel experiments, GRIP-1 silencing significantly reduced GR-mediated transactivation activities. Co-immunoprecipitation and GST pull-down assays showed that GRIP-1, through its repression domain, physically interacts with IRF-1 identifying GRIP-1 as a bona fide transcriptional co-activator for IRF-1. Interestingly, the previously reported inhibition of GR-mediated transactivation activities by either TNF- and IFN- treatment or IRF-1 overexpression was fully reversed by increasing cellular levels of GRIP-1. Together, these data suggest that the cellular accumulation of IRF-1 may represent a potential molecular mechanism mediating altered cellular response to GC through the depletion of GRIP-1 from the GR transcriptional regulatory complexes.

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Citation

American Journal of Respiratory Cell and Molecular Biology, 2010, 42(1), pp.9-15.

Published in

American Journal of Respiratory Cell and Molecular Biology

Publisher

American Thoracic Society

issn

1044-1549

Copyright date

2010

Available date

25/06/2010

Publisher version

http://www.atsjournals.org/doi/abs/10.1165/rcmb.2009-0239RC

Language

en

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