Cyclin-Dependent Kinase 5 Differentially Regulates the Transcriptional Activity of the Glucocorticoid Receptor through Phosphorylation: Clinical Implications for the Nervous System Response to Glucocorticoids and Stress

Kino, Tomoshige; Ichijo, Takamasa; Amin, Niranjana D.; Kesavapany, Sashi; Wang, Yonghong; Kim, Nancy; Rao, Sandesh; Player, Audrey; Zheng, Yali; Garabedian, Michael J.; Kawasaki, Ernest S.; Pant, Harish C.; Chrousos, George P.

doi:10.1210/me.2006-0345

Cited by 113 publications

(125 citation statements)

References 63 publications

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“…This suggests that GR phosphorylation at S203 serves as a negative regulator of GR transcriptional activity in ASM cells. A similar observation was reported by Kino and colleagues, who found that the GR-S203A mutant dramatically increased GC-induced, GRmediated transactivation activities in human colorectal carcinoma cell line (HCT116) (45). Other differences found in our study are the fact that GR phosphorylation at S203 was mostly located in the cytoplasm of ASM cells (data not shown) and that the transfection of the mutated form of GR at S203 residues was associated with increased GR nuclear translocation ( Figure 4B).…”

Section: Discussionsupporting

confidence: 85%

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

Bouazza

Debba-Pavard²,

Amrani³

et al. 2014

Am J Respir Cell Mol Biol

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Like many steroid receptors, the glucocorticoid (GC) receptor (GR) is a phosphoprotein. Although there are multiple phosphorylation sites critical for GR transcriptional activity (i.e., serine [S]203, S211, and S226), their respective role in driving GR functions is highly cell specific. We have recently identified protein phosphatase 5 as an essential Ser/Thr phosphatase responsible for impairing GR function via S211 dephosphorylation in airway smooth muscle (ASM) cells. Because p38 mitogen-activated protein kinase (MAPK) directly phosphorylates GR in different cell types in a stimulus-and celldependent manner, we investigated the role of p38 MAPK on GR phosphorylation and function in ASM cells. Cells were transfected with 100 nM p38 MAPK small interfering RNA or 2 mg MAPK kinase 3 expression vector (a specific kinase that directly activates p38 MAPK) in the presence or absence of fluticasone (100 nM) and/or p38 MAPK pharmacological inhibitor SB203580. We found that p38 MAPK blockade positively regulates GR nuclear translocation and GR-dependent induction of the steroid-target gene GC-induced leucine zipper in a hormone-independent manner. We also found that p38 MAPK-dependent regulation of GR functions was associated with a differential action on GR phosphorylation at S203 and S211 residues. This study demonstrated that the inactive state of GR in resting conditions is not only ensured by the absence of the GC ligand but also by p38 MAPK-dependent phosphorylation of unliganded GR at specific residues, which appears to be important in determining the overall GC responsiveness of ASM cells.

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Section: Discussionsupporting

confidence: 85%

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

Bouazza

Debba-Pavard²,

Amrani³

et al. 2014

Am J Respir Cell Mol Biol

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“…Mechanisms resulting in GC resistance are rarely attributed to mutation of the GR but often attributed to the convergence of additional activated cell signaling components with the GR pathway. Such pathways include mitogen-activated kinases, protein kinase A, CDKs, and receptor tyrosine kinase (2,26,32,39,44). We show here the convergence of another pathway, the GSK-3␤ signaling pathway, which also exerts a form of cellular resistance to GC administration.…”

Section: Discussionmentioning

confidence: 61%

“…However, in addition to ligand binding, several recent studies provide evidence that cross talk from other signaling pathways are able to directly modulate the GR transcriptional responses by phosphorylating the GR (17). In fact, human GR phosphorylation by kinases, such as mitogen-activated protein kinases and cyclin-dependent kinases (CDKs), act to modulate the receptor protein stability, subcellular localization, protein interactions, and translational response (12,26,28,32,39,44,48). Interestingly, Rogatsky et al have previously shown that GSK-3␤-mediated phosphorylation of rat GR on threonine 171 can inhibit transcriptional activation (40).…”

mentioning

confidence: 99%

Glycogen Synthase Kinase 3β-Mediated Serine Phosphorylation of the Human Glucocorticoid Receptor Redirects Gene Expression Profiles

Galliher-Beckley¹,

Williams²,

Collins

et al. 2008

Molecular and Cellular Biology

114

102

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Aberrant glycogen synthase kinase 3␤ (GSK-3␤) activity is associated with the progression of several pathological conditions such as diabetes, Alzheimer's, and cancer. GSK-3␤ regulates cellular processes by directly phosphorylating metabolic enzymes and transcription factors. Here, we discovered a new target for GSK-3␤ phosphorylation: the human glucocorticoid receptor (GR). Glucocorticoid signaling is essential for life and regulates diverse biological functions from cell growth to metabolism to apoptosis. Specifically, we found hormone-dependent GR phosphorylation on serine 404 by GSK-3␤. Cells expressing a GR that is incapable of GSK-3␤ phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-B. Furthermore, GSK-3␤-mediated GR phosphorylation inhibited glucocorticoid-dependent NF-B transrepression and attenuated the glucocorticoid-dependent cell death of osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3␤ and the GR pathways, resulting in altered hormone-regulated signaling. Our results also provide a mechanism by which GSK-3␤ activity can dictate how cells will ultimately respond to glucocorticoids.

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“…Other kinases are also reported as candidates for phosphorylating AR Ser-81 site, such as Cdk1, Cdk5 (5,8), and Cdk9 (5). With regard to Cdk5, it has been reported to regulate the transcriptional activity of glucocorticoid receptor through phosphorylation (37). In addition, there is evidence indicating that the amino acid sequence of the N terminus of Cdk5 contains the LXXLL motif, which corresponds to the sequence that cofactors utilize for interaction with nuclear receptors (38).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Androgen Receptor and Prostate Cancer Growth by Cyclin-dependent Kinase 5

Hsu

Chen

Chiang

et al. 2011

Journal of Biological Chemistry

114

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Prostate cancer is the most frequently diagnosed male malignancy. The normal prostate development and prostate cancer progression are mediated by androgen receptor (AR). Recently, the roles of cyclin-dependent kinase 5 (Cdk5) and its activator, p35, in cancer biology are explored one after another. We have previously demonstrated that Cdk5 may regulate proliferation of thyroid cancer cells. In addition, we also identify that Cdk5 overactivation can be triggered by drug treatments and leads to apoptosis of prostate cancer cells. The aim of this study is to investigate how Cdk5 regulates AR activation and growth of prostate cancer cells. At first, the data show that Cdk5 enables phosphorylation of AR at Ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of AR proteins. The Cdk5-dependent AR stabilization causes accumulation of AR proteins and subsequent activation. Besides, the positive regulations of Cdk5-AR on cell growth are also determined in vitro and in vivo. S81A mutant of AR diminishes its interaction with Cdk5, reduces its nuclear localization, fails to stabilize its protein level, and therefore, decreases prostate cancer cell proliferation. Prostate carcinoma specimens collected from 177 AR-positive patients indicate the significant correlations between the protein levels of AR and Cdk5 or p35. These findings demonstrate that Cdk5 is an important modulator of AR and contributes to prostate cancer growth. Therefore, Cdk5-p35 may be suggested as diagnostic and therapeutic targets for prostate cancer in the near future.Prostate cancer is a commonly diagnosed malignancy in men, and androgen plays an important role in its early development (1). Androgen deprivation has been considered as a common therapy for androgen-dependent prostate cancer. However, the existing cancer cells eventually become hormone-refractory, and the following therapy usually gets into scrapes. The androgen receptor (AR), 2 which belongs to the steroid receptor family and plays pivotal roles in the development of the prostate gland and the pathogenic progression of prostate cancer. High levels of AR expression along with its target genes have been reported in hormone-refractory prostate cancer cells, suggesting that AR signaling is activated regardless of the levels of serum androgen (2). A study analyzing consensus sequences of phosphorylation indicates that AR contains more than 40 predicted phosphorylation sites (3). Ser-81 of the AR N terminus is the most intensely phosphorylated site in response to androgen binding (4). The latest report reveals the relevance of Ser-81 phosphorylation and AR promoter selectivity as well as cell growth (5). Our recent work also shows the increase of Ser-81 phosphorylation of AR in the androgen-independent LNCaP sub-line (6). Fu et al. (7) proposed that the phosphorylation consensus sequence (SPRT) of cyclin-dependent kinase 5 (Cdk5) corresponds with the sequence around AR Ser-81. Although AR was reported as substrates for Cdk9 (5) as well as Cdk1 (8), whi...

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Cyclin-Dependent Kinase 5 Differentially Regulates the Transcriptional Activity of the Glucocorticoid Receptor through Phosphorylation: Clinical Implications for the Nervous System Response to Glucocorticoids and Stress

Cited by 113 publications

References 63 publications

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

Basal p38 Mitogen-Activated Protein Kinase Regulates Unliganded Glucocorticoid Receptor Function in Airway Smooth Muscle Cells

Glycogen Synthase Kinase 3β-Mediated Serine Phosphorylation of the Human Glucocorticoid Receptor Redirects Gene Expression Profiles

Regulation of Androgen Receptor and Prostate Cancer Growth by Cyclin-dependent Kinase 5

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