Glucocorticoid-Dependent Phosphorylation of the Transcriptional Coregulator GRIP1 Jana Dobrovolna a , Yurii Chinenov a , Megan A. Kennedy a , Bill Liu a and Inez Rogatsky a , b a Hospital for Special Surgery b Department of Microbiology & Immunology, Weill Medical College of Cornell University, New York, New York, USA ABSTRACT Much of the regulatory diversity in eukaryotic transcription is provided by coregulators, which are recruited by DNA-binding factors to propagate signaling to basal machinery or chromatin. p160 family members, including the glucocorticoid receptor (GR)-interacting protein 1 (GRIP1), function as coactivators for GR, a ligand-dependent transcription factor of the nuclear receptor superfamily. Unlike other p160s, GRIP1 also potentiates GR-mediated repression of AP1 and NF-κB targets and, surprisingly, transcriptional activation by interferon regulatory factors. What enables GRIP1 activating or repressing properties or discrimination between physiologically antagonistic pathways is unknown. We found that endogenous GRIP1 in mammalian cells undergoes glucocorticoid-induced, GR interaction-dependent phosphorylation and identified one constitutive and six inducible phosphorylation sites and two putative GRIP1 kinases, casein kinase 2 and cyclin-dependent kinase 9. We raised phosphospecific antibodies to the four closely spaced sites in a previously uncharacterized part of GRIP1 which, combined with mutagenesis, revealed the conservation of GRIP1 phosphorylation across several cell types and species and its functional relevance to GR-activated transcription and to response element-specific recruitment of phospho-GRIP1 to native GR targets. We propose that cofactor engagement by GR is neither passive nor stochastic; rather, GR actively imparts modifications that dictate GRIP1 function in a subset of complexes, adding a layer of specificity to GR transcriptional control.
Glucocorticoid-Dependent Phosphorylation of the Transcriptional Coregulator GRIP1
Abstract
Glucocorticoid-Dependent Phosphorylation of the Transcriptional Coregulator GRIP1 Jana Dobrovolna a , Yurii Chinenov a , Megan A. Kennedy a , Bill Liu a and Inez Rogatsky a , b a Hospital for Special Surgery b Department of Microbiology & Immunology, Weill Medical College of Cornell University, New York, New York, USA ABSTRACT Much of the regulatory diversity in eukaryotic transcription is provided by coregulators, which are recruited by DNA-binding factors to propagate signaling to basal machinery or chromatin. p160 family members, including the glucocorticoid receptor (GR)-interacting protein 1 (GRIP1), function as coactivators for GR, a ligand-dependent transcription factor of the nuclear receptor superfamily. Unlike other p160s, GRIP1 also potentiates GR-mediated repression of AP1 and NF-κB targets and, surprisingly, transcriptional activation by interferon regulatory factors. What enables GRIP1 activating or repressing properties or discrimination between physiologically antagonistic pathways is unknown. We found that endogenous GRIP1 in mammalian cells undergoes glucocorticoid-induced, GR interaction-dependent phosphorylation and identified one constitutive and six inducible phosphorylation sites and two putative GRIP1 kinases, casein kinase 2 and cyclin-dependent kinase 9. We raised phosphospecific antibodies to the four closely spaced sites in a previously uncharacterized part of GRIP1 which, combined with mutagenesis, revealed the conservation of GRIP1 phosphorylation across several cell types and species and its functional relevance to GR-activated transcription and to response element-specific recruitment of phospho-GRIP1 to native GR targets. We propose that cofactor engagement by GR is neither passive nor stochastic; rather, GR actively imparts modifications that dictate GRIP1 function in a subset of complexes, adding a layer of specificity to GR transcriptional control.Preview Only. This article cannot be rented because we do not currently have permission from the publisher.
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Glucocorticoid-Dependent Phosphorylation of the Transcriptional Coregulator GRIP1
Dobrovolna, Jana; Chinenov, Yurii; Kennedy, Megan A.; Liu, Bill; Rogatsky, Inez
Follow Molecular and Cellular Biology
, Volume 32 (4): 730
American Society For Microbiology – Feb 15, 2012
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