Intersection of nuclear receptors and the proteasome on the epigenetic landscape

Kinyamu, H. Karimi; Jefferson, Wendy N.; Archer, Trevor

doi:10.1002/em.20360

Cited by 23 publications

(25 citation statements)

References 132 publications

(235 reference statements)

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“…This would be consistent with the large body of evidence that the proteasome and its proteolytic activity play a major role in cellular transcription (9,20,41) as well as the studies linking proteasome activity with viral transcription. At this time, we cannot exclude a nonproteolytic role for specific subunits, as the 19S subunits also possess chaperone activities and can aid in remodeling protein complexes during transcription, modifying histones, and recruiting cotransactivator complexes (9,13,20,32,34,40). The HIV-1 promoter is a notable example of transcription regulation mediated by both proteolytic and nonproteolytic mechanisms (33,42,43,55).…”

Section: Discussionmentioning

confidence: 99%

“…These processes include cell cycle regulation, signal transduction, apoptosis, and antigen presentation, among others (11,14). Numerous studies have also linked the UPS to transcription regulation, DNA repair, and chromatin remodeling, at both a proteolytic and nonproteolytic level (9,13,32,34,40,49). Thus, its potential role in disease pathogenesis has also been an area of great interest.…”

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confidence: 99%

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Proteasome Subunits Relocalize during Human Cytomegalovirus Infection, and Proteasome Activity Is Necessary for Efficient Viral Gene Transcription

Tran

Mahr

Spector

2010

J Virol

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We have continued studies to further understand the role of the ubiquitin-proteasome system (UPS) in human cytomegalovirus (HCMV) infection. With specific inhibitors of the proteasome, we show that ongoing proteasome activity is necessary for facilitating the various stages of the infection. Immediate-early protein 2 expression is modestly reduced with addition of proteasome inhibitors at the onset of infection; however, both early and late gene expression are significantly delayed, even if the inhibitor is removed at 12 h postinfection. Adding the inhibitor at later times during the infection blocks the further accumulation of viral early and late gene products, the severity of which is dependent on when the proteasome is inhibited. This can be attributed primarily to a block in viral RNA transcription, although DNA synthesis is also partially inhibited. Proteasome activity and expression increase as the infection progresses, and this coincides with the relocalization of active proteasomes to the periphery of the viral DNA replication center, where there is active RNA transcription. Interestingly, one 19S subunit, Rpn2, is specifically recruited into the viral DNA replication center. The relocalization of the subunits requires viral DNA replication, but their maintenance around or within the replication center is not dependent on continued viral DNA synthesis or the proteolytic activity of the proteasome. These studies highlight the importance of the UPS at all stages of the HCMV infection and support further studies into this pathway as a potential antiviral target.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Proteasome Subunits Relocalize during Human Cytomegalovirus Infection, and Proteasome Activity Is Necessary for Efficient Viral Gene Transcription

Tran

Mahr

Spector

2010

J Virol

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“…The correct regulation of the onset of ZGA is an important process for remodeling of an oocyte to a totipotent zygote. Recently, several studies have implicated the UPS in the regulation of transcription [14][15][16][17]. These observations led us to investigate a potential link between the UPS and onset of ZGA in early mouse embryos.…”

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confidence: 99%

Inhibition of the Ubiquitin-proteasome System Leads to Delay of the Onset of ZGA Gene Expression

et al. 2010

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Abstract. In mammalian oocytes, the ubiquitin-proteasome system (UPS) is suggested to play important roles in oocyte meiosis resumption, spindle assembly, polar body emission and pronuclear formation by regulating cyclin B1 degradation. However, little is known about the direct relationship between zygotic gene activation (ZGA) and degradation of maternal proteins. Here, we investigated the role of the UPS in the onset of ZGA in early mouse embryos. First, we found degradation of cyclin B1 protein in fertilized oocytes at 1 hpi by western blot analysis and used these oocytes throughout this study. Subsequently, we determined optimal experimental conditions for transient inhibition of proteasomal activity by specific and reversible proteasomal inhibitor MG132 in the G1 phase of the first cell cycle. Under the selected optimal conditions, we subjected transient MG132-treated embryos to reverse transcription (RT)-PCR analysis of expression of four ZGA genes, i.e., the hsp70.1, MuERV-L, eif-1a and zscan4d genes. As a result, we found that onset of expression of the four examined ZGA genes was delayed in both normally developed 2-cell embryos and arrested 1-cell embryos. Our results indicate that proteasomal degradation of proteins by the UPS plays a pivotal role in the molecular mechanisms of ZGA in early mouse embryos. Key words: Early embryo, MG132, Mouse, Ubiquitin-proteasome system, Zygotic gene activation (J. Reprod. Dev. 56: [655][656][657][658][659][660][661][662][663] 2010) he proteasome is a large protein complex for degradation of most intracellular proteins in eukaryotic cells [1,2]. For proteasomal degradation, the substrate proteins are required for tagging by ubiquitin. Generally, the ubiquitin-proteasome system (UPS) is involved in a wide variety of biological processes, including DNA repair, apoptosis, immune response, signal transduction, transcription, metabolism, protein quality control and developmental programs [3,4].In mammalian oocytes, the UPS is suggested to play important roles in oocyte meiosis resumption, spindle assembly, polar body emission and pronuclear formation by regulating cyclin B1 degradation [5][6][7]. Ubiquitin enzyme E1 [8], E2 [9] and E3 [10] are active during mammalian spermatogenesis, suggesting that the UPS may play roles during spermatogenesis [11]. In fertilization, ubiquitination of the sperm mitochondrial membranes may assist in destruction of paternal mitochondria at fertilization for promoting the maternal inheritance of mitochondrial DNA in mammals [11,12].In mouse embryos, the onset of zygotic gene activation (ZGA) has been shown to occur after fertilization and is a critical event that governs the maternal-to-zygotic transition (MZT) for embryonic development [13]. The correct regulation of the onset of ZGA is an important process for remodeling of an oocyte to a totipotent zygote. Recently, several studies have implicated the UPS in the regulation of transcription [14][15][16][17]. These observations led us to investigate a potential link between the UPS and ...

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“…A generalized view of transcription activation by nuclear receptors such as GR has emerged where, upon hormone binding, GR dimerizes and is targeted to its cognate hormone response elements within chromatin. Ligand binding induces a conformational change in the GR that allows it to recruit various coactivators to remodel chromatin and increase accessibility of general transcription factors to GR target genes to initiate transcription (8,21,22).…”

Section: Discussionmentioning

confidence: 99%

Differential Glucocorticoid Receptor-mediated Transcription Mechanisms

Archer

2011

Journal of Biological Chemistry

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Nuclear receptors such as the glucocorticoid receptor (GR) are ligand-dependent transcription factors that mediate transcription of target genes by recruiting factors that modulate chromatin structure. In this study, curcumin, a compound known to inhibit GR-mediated transcription, was used to examine the different mechanisms by which GR regulates transcription. The mechanisms of transcription regulation of metallothioneine-2A (MT2A) and solute carrier family 19 member 2 (SLC19A2), two GR target genes where the hormone-dependent gene activation is inhibited or unaffected by curcumin treatment, respectively, were analyzed by chromatin immunoprecipitation and RT-PCR experiments. The data suggest that the loss of hormone-dependent MT2A gene expression is due to the inhibition of continued transcription activity after initial assembly of the transcription machinery. In contrast, the hormone-dependent SLC19A2 gene expression is maintained because the continued transcription output after assembly of transcription machinery is unaffected by curcumin. These results suggest that the two GR target genes use alternate mechanisms to regulate expression levels at the level of continued transcription output after transcription machinery assembly.

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Intersection of nuclear receptors and the proteasome on the epigenetic landscape

Cited by 23 publications

References 132 publications

Proteasome Subunits Relocalize during Human Cytomegalovirus Infection, and Proteasome Activity Is Necessary for Efficient Viral Gene Transcription

Proteasome Subunits Relocalize during Human Cytomegalovirus Infection, and Proteasome Activity Is Necessary for Efficient Viral Gene Transcription

Inhibition of the Ubiquitin-proteasome System Leads to Delay of the Onset of ZGA Gene Expression

Differential Glucocorticoid Receptor-mediated Transcription Mechanisms

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