A Vitamin D Receptor/SMAD Genomic Circuit Gates Hepatic Fibrotic Response

Ding, Ning; Yu, Ruth T.; Subramaniam, Nanthakumar; Sherman, Mara H.; Wilson, Caroline; Rao, Renuka; Leblanc, Mathias; Coulter, Sally; He, Min; Scott, Carolyn D.; Lau, Sue Lynn; Atkins, Annette R.; Barish, Grant D.; Gunton, Jenny E.; Liddle, Christopher; Downes, Michael; Evans, Ronald M.

doi:10.1016/j.cell.2013.03.028

Cited by 533 publications

(495 citation statements)

References 68 publications

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“…Furthermore, our findings suggested that overexpression of VDR impaired the decrease of E-cadherin and the increase of a-SMA normally observed in 4T1 cells following coculture with macrophages. This loss of epithelial markers with a concurrent increase in mesenchymal markers is the key indicator for EMT (23,24), which is regarded as a critical pathologic event in the initiation and promotion of metastasis (1). Therefore, our findings suggest that the loss of VDR is likely required for the prometastatic effect of TAMs.…”

Section: Discussionmentioning

confidence: 55%

VDR Status Arbitrates the Prometastatic Effects of Tumor-Associated Macrophages

Zhang¹,

Guo²,

Zhang

et al. 2014

Molecular Cancer Research

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The relationship between tumor-associated macrophages (TAM) and epithelial-to-mesenchymal transition (EMT) during the initiation and progression of metastasis is still unclear. Here, a role for the vitamin D receptor (VDR) in metastasis was identified, as well as a role in the relationship between TAMs and EMT. First, the expression level of VDR was examined in clinical tissue from human patients with breast cancer or a mouse model of breast cancer with differential metastasis. These results revealed that VDR expression negatively correlates with metastasis in breast cancer. Second, coculture of VDR-overexpressing breast cancer cells with a macrophage cell line demonstrated that overexpression of VDR alleviated the prometastatic effect of cocultured macrophages on breast cancer cells. Furthermore, VDR overexpression abrogated the induction of EMT in breast cancer cells by cocultured macrophage cells, as measured by a loss of E-cadherin (CDH1) and induction of a-smooth muscle actin (a-SMA). TNFa in macrophage conditioned media inhibited VDR expression, whereas downregulation of VDR further mediated the promotion of TGFb-induced EMT by TNFa. In addition, b-catenin expression was inhibited in VDR-overexpressing breast cancer cells and tumor xenografts.

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Section: Discussionmentioning

confidence: 55%

VDR Status Arbitrates the Prometastatic Effects of Tumor-Associated Macrophages

Zhang¹,

Guo²,

Zhang

et al. 2014

Molecular Cancer Research

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“…Recently, it has been reported that other ligands of nuclear receptors can also repress fibrosis. In particular, vitamin D receptor signaling prevents CCl4-induced liver fibrosis, inhibiting SMAD3 occupancy and SMAD-dependent transcriptional activity (56). Furthermore, vitamin D receptor agonists without hypercalcemic effects showed antifibrotic activity (57).…”

Section: Discussionmentioning

confidence: 99%

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

Alonso-Merino

Orozco

Ruíz-Llorente

et al. 2016

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

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TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMADbinding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.This work was supported by Grants BFU2011-28058 and BFU2014-53610P from Ministerio de Economía y Competitividad; S2011/BMD-2328 TIRONET from the Comunidad de Madrid; and RD12/0036/0030 from the Instituto de Salud Carlos III. The cost of this publication has been paid in part by FEDER fund

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“…TGF-b signaling also cooperates with the Hippo pathway through interactions between the SMADs and TAZ/YAP (Varelas et al 2008). Finally, SMADs have been shown to actively direct the binding of other transcriptional regulators, as in the context of the TGF-b-induced liver fibrotic response in which TGF-b-induced SMAD3 directs the binding of ligand-bound nuclear vitamin D receptor (Ding et al 2013).…”

Section: Smad-interacting Transcription Factorsmentioning

confidence: 99%

Transcriptional Control by the SMADs

Hill

2016

Cold Spring Harb Perspect Biol

289

256

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The transforming growth factor-b (TGF-b) family of ligands elicit their biological effects by initiating new programs of gene expression. The best understood signal transducers for these ligands are the SMADs, which essentially act as transcription factors that are activated in the cytoplasm and then accumulate in the nucleus in response to ligand induction where they bind to enhancer/promoter sequences in the regulatory regions of target genes to either activate or repress transcription. This review focuses on the mechanisms whereby the SMADs achieve this and the functional implications. The SMAD complexes have weak affinity for DNA and limited specificity and, thus, they cooperate with other site-specific transcription factors that act either to actively recruit the SMAD complexes or to stabilize their DNA binding. In some situations, these cooperating transcription factors function to integrate the signals from TGF-b family ligands with environmental cues or with information about cell lineage. Activated SMAD complexes regulate transcription via remodeling of the chromatin template. Consistent with this, they recruit a variety of coactivators and corepressors to the chromatin, which either directly or indirectly modify histones and/or modulate chromatin structure.

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A Vitamin D Receptor/SMAD Genomic Circuit Gates Hepatic Fibrotic Response

Cited by 533 publications

References 68 publications

VDR Status Arbitrates the Prometastatic Effects of Tumor-Associated Macrophages

VDR Status Arbitrates the Prometastatic Effects of Tumor-Associated Macrophages

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

Transcriptional Control by the SMADs

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