<i>O</i>-GlcNAc Integrates the Proteasome and Transcriptome To Regulate Nuclear Hormone Receptors

Bowe, Damon B.; Sadlonova, Andrea; Toleman, Clifford A.; Novák, Zdeněk; Hu, Yong; Huang, Ping; Mukherjee, Shibani; Whitsett, Timothy G.; Frost, Andra R.; Paterson, Andrew J.; Kudlow, Jeffrey E.

doi:10.1128/mcb.01053-06

Cited by 34 publications

(39 citation statements)

References 35 publications

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“…Hsp90b also contributes to protecting the ER against the UP pathway (29), whereas dynein light chain has been recently shown to link nER to other chromatin remodeling complexes (22). In contrast, O-GlcNAc transferase and UCE2 variant 1 and other proteins including ubiquitin thiolesterase, ubiquitin c-terminal hydrolase L1, cdc23, and SMT3 suppressor of MIF two 3 homolog 3 (functional theme U in Table 2) are all functionally related to the UP degradation pathway, which regulates nER stability (7,39,59). The differential expression of these modulatory factors after fadrozole treatments suggests an autoregulation mechanism of E2 action in the neuroendocrine brain.…”

Section: Discussionmentioning

confidence: 99%

Profiling neuroendocrine gene expression changes following fadrozole-induced estrogen decline in the female goldfish

Zhang

Popesku

Martyniuk

et al. 2009

Physiological Genomics

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Teleost fish represent unique models to study the role of neuroestrogens because of the extremely high activity of brain aromatase (AroB; the product of cyp19a1b). Aromatase respectively converts androstenedione and testosterone to estrone and 17␤-estradiol (E2). Specific inhibition of aromatase activity by fadrozole has been shown to impair estrogen production and influence neuroendocrine and reproductive functions in fish, amphibians, and rodents. However, very few studies have identified the global transcriptomic response to fadrozole-induced decline of estrogens in a physiological context. In our study, sexually mature prespawning female goldfish were exposed to fadrozole (50 g/l) in March and April when goldfish have the highest AroB activity and maximal gonadal size. Fadrozole treatment significantly decreased serum E2 levels (4.7 times lower; P ϭ 0.027) and depressed AroB mRNA expression threefold in both the telencephalon (P ϭ 0.021) and the hypothalamus (P ϭ 0.006). Microarray expression profiling of the telencephalon identified 98 differentially expressed genes after fadrozole treatment (q value Ͻ0.05). Some of these genes have shown previously to be estrogen responsive in either fish or other species, including rat, mouse, and human. Gene ontology analysis together with functional annotations revealed several regulatory themes for physiological estrogen action in fish brain that include the regulation of calcium signaling pathway and autoregulation of estrogen receptor action. Real-time PCR verified microarray data for decreased (activin-␤A) or increased (calmodulin, ornithine decarboxylase 1) mRNA expression. These data have implications for our understanding of estrogen actions in the adult vertebrate brain.aromatase; microarray; fish; brain MAIN ESTROGENS estradiol-17␤ (E2) and estrone (E1) play fundamental regulatory roles in neuroendocrine and reproductive systems. Through binding to its nuclear estrogen receptors (nER)-␣ and nER-␤, E2 regulates transcriptional process of target genes whose promoters contain estrogen-responsive elements (ERE) (57). In addition to this classical nuclear action, E2 also has membrane actions in which a unique membrane receptor is utilized to rapidly activate a series of signaling pathways (52,70). Since the signaling pathway activation will ultimately influence the transcriptional activities of downstream transcription factors including nERs, membrane actions of E2 provide another mode to regulate genomic gene expression (70). Fish are unique models in which to study E2 action because there is high activity of the B-subtype aromatase (AroB; the product of cyp19a1b), the enzyme responsible for synthesizing E2 from testosterone (T), in the neuroendocrine brain, telencephalon (Tel) and hypothalamus (Hyp) (42). Moreover, in contrast to mammals where aromatase and nER are commonly expressed in neurons, current studies in fish and birds strongly suggest that AroB is exclusively expressed in radial glial cells and nER is mostly expressed in neurons (16,43). Thus, the local...

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Section: Discussionmentioning

confidence: 99%

Profiling neuroendocrine gene expression changes following fadrozole-induced estrogen decline in the female goldfish

Zhang

Popesku

Martyniuk

et al. 2009

Physiological Genomics

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“…Thus, it seems that the phosphorylation sites being targeted determine the final effect. Proteasomes can be also modified by O-linked N-acetylglucosamine modifications (Bowe et al, 2006). Specifically, the Rpt2 subunit can be modified by O-linked N-acetylglucosamine that results in reduced proteasome functionality .…”

Section: Subcellular Localization and Regulation Of The Proteasomementioning

confidence: 99%

The Amazing Ubiquitin-Proteasome System: Structural Components and Implication in Aging

Tsakiri

Trougakos

2015

International Review of Cell and Molecular Biology

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“…This protein binds along with histone deacetylases in corepressor complexes to repress gene transcription of selected genes (31). OGT has been shown to copurify with NCoR in these complexes (32). It is proposed that the binding of OGT with the corepressor complex allows targeting of the enzyme to promoter regions, where it modifies transcriptional machinery such as RNA polymerase II and transcription factors.…”

Section: Functions Of the Identified O-glcnac-modified Proteinsmentioning

confidence: 99%

Identification of protein O-GlcNAcylation sites using electron transfer dissociation mass spectrometry on native peptides

Chalkley

Thalhammer

Schoepfer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

217

236

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Protein O-GlcNAcylation occurs in all animals and plants and is implicated in modulation of a wide range of cytosolic and nuclear protein functions, including gene silencing, nutrient and stress sensing, phosphorylation signaling, and diseases such as diabetes and Alzheimer's. The limiting factor impeding rapid progress in deciphering the biological functions of protein O-GlcNAcylation has been the inability to easily identify exact residues of modification. We describe a robust, high-sensitivity strategy able to assign O-GlcNAcylation sites of native modified peptides using electron transfer dissociation mass spectrometry. We have studied the murine postsynaptic density pseudoorganelle and report the assignment of 58 modification sites from a single experiment-significantly increasing the number of sites known in the literature. Components of several repressor complexes, such as NCoR1, polyhomeotic-like protein3, and EMSY, are modified. In addition, 28 O-GlcNAc sites were found on the protein Bassoon, effectively matching the number of phosphorylation sites reported previously on this protein. This finding suggests that on certain proteins, O-GlcNAcylation may be as extensive and important as phosphorylation in regulating protein function. Three of the newly discovered O-GlcNAc sites on Bassoon have previously been reported as phosphorylation sites, highlighting the interplay of the modifications. Surprisingly, several peptides with GlcNAc modifications on asparagines within the N-X-S/T consensus sequence were also observed from membrane protein extracellular domains. This powerful strategy fulfills a long-standing need in the biological community by facilitating modification site identifications that will accelerate understanding of the biological significance of this elusive regulatory posttranslational modification. modification site assignment ͉ posttranslational modification ͉ proteomics ͉ Bassoon

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O-GlcNAc Integrates the Proteasome and Transcriptome To Regulate Nuclear Hormone Receptors

Cited by 34 publications

References 35 publications

Profiling neuroendocrine gene expression changes following fadrozole-induced estrogen decline in the female goldfish

Profiling neuroendocrine gene expression changes following fadrozole-induced estrogen decline in the female goldfish

The Amazing Ubiquitin-Proteasome System: Structural Components and Implication in Aging

Identification of protein O-GlcNAcylation sites using electron transfer dissociation mass spectrometry on native peptides

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