Glucocorticoid receptor inhibits transforming growth factor-β signaling by directly targeting the transcriptional activation function of Smad3

Song, Chao; Xiang, Tian; Gelehrter, Thomas D.

doi:10.1073/pnas.96.21.11776

Cited by 166 publications

(126 citation statements)

References 57 publications

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“…Plasmids-The TRS reporter plasmid, pTRS6E1B-luc, contains six copies of the TRS at Ϫ732/Ϫ721 of the human PAI-1 promoter upstream of an E1B TATA box linked to a luciferase reporter gene (28,37). The human GR expression plasmid (pRShGR␣) and GR deletion mutants were kindly provided by Dr. R. Evans (Salk Institute) (41).…”

Section: Methodsmentioning

confidence: 99%

“…The c deletion mutant GR1-726 was constructed by digesting pZP-hGR with NsiI, followed by self-ligation of the 6342-bp fragment. The GRE expressing reporter plasmid pGRE4E1b-luc was constructed by inserting four copies of a 15-bp GRE from the rat tyrosine aminotransferase gene upstream of the E1bTATA box of pE1b-luc (37).…”

Section: Methodsmentioning

confidence: 99%

“…We have previously reported that liganded GR repressed TGF-␤ transcriptional activation of both the PAI-1 promoter and a multimerized TGF-␤-responsive sequence (TRS) of the PAI-1 promoter containing Smad3/4 binding sites. We also showed that liganded GR repressed transactivation by the Smad3 and Smad4 C-terminal activation domains, and that GR physically interacted with Smad3 both in vitro and in vivo (37). In this report, we characterize the GR domain(s) responsible for the repression of TGF-␤ transactivation of the human PAI-1 gene and further investigate the GR domain(s) involved in the physical interaction between GR and Smad3 and the correlation between physical interaction and transrepression.…”

mentioning

confidence: 99%

“…Glucocorticoids inhibit the TGF-␤-induced expression of extracellular matrix proteins including fibronectin, collagen, tissue inhibitors of metalloproteinases, and human PAI-1 (37)(38)(39)(40). Hence, glucocorticoids and TGF-␤ may be important opposing physiological regulators of wound healing and fibrosis.…”

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confidence: 99%

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Identification of Glucocorticoid Receptor Domains Involved in Transrepression of Transforming Growth Factor-β Action

Wang

Gelehrter

2003

Journal of Biological Chemistry

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The transforming growth factor-␤ (TGF-␤) and glucocorticoid signaling pathways interact both positively and negatively in regulating a variety of physiological and pathologic processes. We previously reported that liganded glucocorticoid receptor (GR) repressed TGF-␤ induction of human plasminogen activator inhibitor-1 gene transcription by directly targeting the transcriptional activation function of Smad3. To identify the domain(s) in the glucocorticoid receptor involved in this repression, we have examined the ability of various GR truncation, deletion, and substitution mutants to repress TGF-␤ transactivation in Hep3B human hepatoma cells that lack functional endogenous GR. Partial deletions in the ligand-binding domain (LBD), including the 2 and c regions, greatly reduced or eliminated GR repression, whereas deletion of the N-terminal AF1 ( 1) domain and substitution mutations in the DNA-binding domain had little or no effect. Liganded androgen receptor repressed TGF-␤ transactivation, whereas mineralocorticoid receptor did not, and studies with rat GRmineralocorticoid receptor chimeras confirmed that the GR C-terminal domains were required for repression. RU486, a strong antagonist of transactivation by GR, partially reversed repression by wild type GR. Co-immunoprecipitation experiments in Hep3B cells indicated that physical interaction between GR and Smad3 is necessary but not sufficient for repression. Physical interaction required activation of Smad3 by TGF-␤ but not dexamethasone binding to GR. Glutathione S-transferase pull-down assays demonstrated that several regions of the LBD could mediate GR-Smad3 physical interaction. We conclude that the LBD of GR, but not the DNAbinding domain or the N-terminal activation domain, is required for GR-mediated transrepression of TGF-␤ transactivation.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Identification of Glucocorticoid Receptor Domains Involved in Transrepression of Transforming Growth Factor-β Action

Wang

Gelehrter

2003

Journal of Biological Chemistry

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“…Thirdly, PP5 has been implicated in the regulation of multiple pathways, including adipogenesis by controlling the GRα and PPARγ phosphorylation (34), DNA-damage repair by controlling the ATM/ATR/Chk1 and p53 pathway components (21,31,34-37), MAPK-mediated growth and differentiation (38)(39)(40)(41)(42)(43)(44), and cell cycle arrest (45). Interestingly, GRα has also been implicated in the repression of the TGFβ pathway by its association with SMAD3 (46). How these roles of PP5 relate to its potential impact on TGFβ pathway is still unknown.…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor‐β pathway

Bruce

Macartney

Yong

et al. 2012

Cellular Signalling

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Protein phosphatases play a key role in balancing cellular responses to transforming growth factor-β (TGFβ) signals. Several protein phosphatases have been attributed roles in the regulation of the TGFβ pathway. Among these, PPM1A is the only phosphatase reported to dephosphorylate SMAD2/3 in the nucleus. However we observed PPM1A exclusively in the cytoplasmic fractions independently of TGFβ treatment in all cells tested. These observations imply that a bona fide nuclear SMAD2/3 phosphatase remains elusive. In this study, we report a role for protein phosphatase 5 (PP5) in the TGFβ pathway. We identified PP5 as an interactor of SMAD2/3. Interestingly, in mouse embryonic fibroblast cells derived from PP5-null mice, TGFβ-induced transcriptional responses were significantly enhanced. This enhancement is due to the increased levels of SMAD3 protein observed in PP5-null MEFs compared to the wild type. No differences in the levels of SMAD3 transcripts were observed between the wild type and PP5-null MEFs. While PP5 is capable of dephosphorylating SMAD3-tail in overexpression assays, we demonstrate that its activity is essential in controlling SMAD3 protein levels in MEFs. We propose that PP5 regulates the TGFβ pathway in MEFs by regulating the expression of SMAD3 protein levels.

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Role of transforming growth factor beta in cancer

2001

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Transforming growth factor beta (TGF-beta) is an effective and ubiquitous mediator of cell growth. The significance of this cytokine in cancer susceptibility, cancer development and progression has become apparent over the past few years. TGF-beta plays various roles in the process of malignant progression. It is a potent inhibitor of normal stromal, hematopoietic, and epithelial cell growth. However, at some point during cancer development the majority of transformed cells become either partly or completely resistant to TGF-beta growth inhibition. There is growing evidence that in the later stages of cancer development TGF-beta is actively secreted by tumor cells and not merely acts as a bystander but rather contributes to cell growth, invasion, and metastasis and decreases host-tumor immune responses. Subtle alteration of TGF-beta signaling may also contribute to the development of cancer. These various effects are tissue and tumor dependent. Identifying and understanding TGF-beta signaling pathway abnormalities in various malignancies is a promising avenue of study that may yield new modalities to both prevent and treat cancer. The nature, prevalence, and significance of TGF-beta signaling pathway alterations in various forms of human cancer as well as potential preventive and therapeutic interventions are discussed in this review.

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Glucocorticoid receptor inhibits transforming growth factor-β signaling by directly targeting the transcriptional activation function of Smad3

Cited by 166 publications

References 57 publications

Identification of Glucocorticoid Receptor Domains Involved in Transrepression of Transforming Growth Factor-β Action

Identification of Glucocorticoid Receptor Domains Involved in Transrepression of Transforming Growth Factor-β Action

Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor‐β pathway

Role of transforming growth factor beta in cancer

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