Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor

Here we report, for the first time, the differential cellular distribution of two melanopsins (Opn4m1 and Opn4m2) and the effects of GR agonist, dexamethasone, on the expression of these opsins and clock genes, in the photosensitiveD. rerioZEM-2S embryonic cells. Immunopositive labeling for Opn4m1 was detected in the cell membrane whereas Opn4m2 labeling shows nuclear localization, which did not change in response to light.opn4m1,opn4m2,gr,per1b,andcry1bpresented an oscillatory profile of expression in LD condition. In both DD and LD condition, dexamethasone (DEX) treatment shifted the peak expression ofper1bandcry1btranscripts to ZT16, which corresponds to the highestopn4m1expression. Interestingly, DEX promoted an increase ofper1bexpression when applied in LD condition but a decrease when the cells were kept under DD condition. Although DEX effects are divergent with different light conditions, the response resulted in clock synchronization in all cases. Taken together, these data demonstrate thatD. rerioZEM-2S cells possess a photosensitive system due to melanopsin expression which results in an oscillatory profile of clock genes in response to LD cycle. Moreover, we provide evidence that glucocorticoid acts as a circadian regulator ofD. rerioperipheral clocks.

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Nuclear and nuclear envelope binding proteins of the glucocorticoid receptor nuclear localization peptide identified by crosslinking

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/0960-0760(91)90193-9 ◽

1991 ◽

Vol 40 (1-3) ◽

pp. 279-285 ◽

Cited By ~ 5

Author(s):

Eric C. LaCasse ◽

Yvonne A. Lefebvre

Keyword(s):

Glucocorticoid Receptor ◽

Nuclear Envelope ◽

Nuclear Localization ◽

Binding Proteins

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REV-ERBα influences stability and nuclear localization of the glucocorticoid receptor

Journal of Cell Science ◽

10.1242/jcs.190959 ◽

2016 ◽

pp. jcs.190959 ◽

Cited By ~ 10

Author(s):

Takashi Okabe ◽

Rohit Chavan ◽

Sara S. Fonseca Costa ◽

Andrea Brenna ◽

Jürgen A. Ripperger ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Nuclear Localization

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Vaccinia-Related Kinase 2 Controls the Stability of the Eukaryotic Chaperonin TRiC/CCT by Inhibiting the Deubiquitinating Enzyme USP25

Molecular and Cellular Biology ◽

10.1128/mcb.01325-14 ◽

2015 ◽

Vol 35 (10) ◽

pp. 1754-1762 ◽

Cited By ~ 21

Author(s):

Sangjune Kim ◽

Dohyun Lee ◽

Juhyun Lee ◽

Haengjin Song ◽

Hyo-Jin Kim ◽

...

Keyword(s):

Protein Aggregation ◽

Ubiquitin Proteasome System ◽

Mutant Protein ◽

Critical Pathway ◽

Interacting Protein ◽

Protein Levels ◽

Functional Regulation ◽

The Stability ◽

And Function ◽

Polyglutamine Protein

Molecular chaperones monitor the proper folding of misfolded proteins and function as the first line of defense against mutant protein aggregation in neurodegenerative diseases. The eukaryotic chaperonin TRiC is a potent suppressor of mutant protein aggregation and toxicity in early stages of disease progression. Elucidation of TRiC functional regulation will enable us to better understand the pathological mechanisms of neurodegeneration. We have previously shown that vaccinia-related kinase 2 (VRK2) downregulates TRiC protein levels through the ubiquitin-proteasome system by recruiting the E3 ligase COP1. However, although VRK2 activity was necessary in TRiC downregulation, the phosphorylated substrate was not determined. Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr680, Thr727, and Ser745residues. Impaired USP25 deubiquitinating activity after VRK2-mediated phosphorylation may be a critical pathway in TRiC protein destabilization.

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Discrimination between NL1- and NL2-Mediated Nuclear Localization of the Glucocorticoid Receptor

Molecular and Cellular Biology ◽

10.1128/mcb.19.2.1025 ◽

1999 ◽

Vol 19 (2) ◽

pp. 1025-1037 ◽

Cited By ~ 140

Author(s):

Joanne G. A. Savory ◽

Brian Hsu ◽

Ian R. Laquian ◽

Ward Giffin ◽

Terry Reich ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Nuclear Localization ◽

Nuclear Import ◽

Nuclear Export ◽

Binding Domain ◽

Leptomycin B ◽

Importin Α ◽

Agonist And Antagonist ◽

Import And Export ◽

Pathway Inhibition

ABSTRACT Glucocorticoid receptor (GR) cycles between a free liganded form that is localized to the nucleus and a heat shock protein (hsp)-immunophilin-complexed, unliganded form that is usually localized to the cytoplasm but that can also be nuclear. In addition, rapid nucleocytoplasmic exchange or shuttling of the receptor underlies its localization. Nuclear import of liganded GR is mediated through a well-characterized sequence, NL1, adjacent to the receptor DNA binding domain and a second, uncharacterized motif, NL2, that overlaps with the ligand binding domain. In this study we report that rapid nuclear import (half-life [t 1/2] of 4 to 6 min) of agonist- and antagonist-treated GR and the localization of unliganded, hsp-associated GRs to the nucleus in G0 are mediated through NL1 and correlate with the binding of GR to pendulin/importin α. By contrast, NL2-mediated nuclear transfer of GR occurred more slowly (t 1/2 = 45 min to 1 h), was agonist specific, and appeared to be independent of binding to importin α. Together, these results suggest that NL2 mediates the nuclear import of GR through an alternative nuclear import pathway. Nuclear export of GR was inhibited by leptomycin B, suggesting that the transfer of GR to the cytoplasm is mediated through the CRM1-dependent pathway. Inhibition of GR nuclear export by leptomycin B enhanced the nuclear localization of both unliganded, wild-type GR and hormone-treated NL1− GR. These results highlight that the subcellular localization of both liganded and unliganded GRs is determined, at least in part, by a flexible equilibrium between the rates of nuclear import and export.

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