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Interaction of vitamin D with membrane-based signaling pathways.

Larriba MJ, González-Sancho JM, Bonilla F, Muñoz A - Front Physiol (2014)

Bottom Line: Moreover, post-transcriptional and post-translational effects of 1α,25(OH)2D3 add to or overlap with its classical modulation of gene transcription rate.Therefore, we propose that future research in the vitamin D field should focus on the interplay between 1α,25(OH)2D3 and agents that act at the plasma membrane, and on the analysis of intercellular communication.Global analyses such as RNA-Seq, transcriptomic arrays, and genome-wide ChIP are expected to dissect the interactions at the gene and molecular levels.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid Madrid, Spain.

ABSTRACT
Many studies in different biological systems have revealed that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) modulates signaling pathways triggered at the plasma membrane by agents such as Wnt, transforming growth factor (TGF)-β, epidermal growth factor (EGF), and others. In addition, 1α,25(OH)2D3 may affect gene expression by paracrine mechanisms that involve the regulation of cytokine or growth factor secretion by neighboring cells. Moreover, post-transcriptional and post-translational effects of 1α,25(OH)2D3 add to or overlap with its classical modulation of gene transcription rate. Together, these findings show that vitamin D receptor (VDR) cannot be considered only as a nuclear-acting, ligand-modulated transcription factor that binds to and controls the transcription of target genes. Instead, available data support the view that much of the complex biological activity of 1α,25(OH)2D3 resides in its capacity to interact with membrane-based signaling pathways and to modulate the expression and secretion of paracrine factors. Therefore, we propose that future research in the vitamin D field should focus on the interplay between 1α,25(OH)2D3 and agents that act at the plasma membrane, and on the analysis of intercellular communication. Global analyses such as RNA-Seq, transcriptomic arrays, and genome-wide ChIP are expected to dissect the interactions at the gene and molecular levels.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the multilevel crosstalk of 1α,25(OH)2D3 (1,25) with Wnt, Hedgehog, and Notch signaling pathways. For simplicity, only main components and regulators of the pathways are shown. Explanations, details, and references can be found in the text.
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Figure 1: Schematic representation of the multilevel crosstalk of 1α,25(OH)2D3 (1,25) with Wnt, Hedgehog, and Notch signaling pathways. For simplicity, only main components and regulators of the pathways are shown. Explanations, details, and references can be found in the text.

Mentions: Wnt factors activate several signaling pathways upon binding to different plasma membrane receptors: the canonical or Wnt/β-catenin and the non-canonical (planar polarity, Ca2+…) pathways (Clevers and Nusse, 2012). Activation of the Wnt/β-catenin pathway by mutation of APC or AXIN tumor suppressor genes or of CTNNB1/β-catenin oncogene together with changes in the expression of a number of regulatory genes (SFRPs, DICKKOPF (DKK)s…) is a hallmark of most colorectal cancers and of a variable proportion of several other malignancies (Clevers and Nusse, 2012). A series of studies report that 1α,25(OH)2D3 antagonizes Wnt/β-catenin signaling in colon cancer cells by several mechanisms: the reduction of transcriptionally active β-catenin/T-cell factor complexes, the induction of β-catenin relocation from the nucleus toward the adherens junctions structures at the plasma membrane, and the increase in the level of the Wnt inhibitor DKK-1 (Pálmer et al., 2001; Shah et al., 2006; Aguilera et al., 2007) (Figure 1). In this way, the pathway endpoint, i.e., the activation of β-catenin target genes, is attenuated by 1α,25(OH)2D3 (Pálmer et al., 2001). Emphasizing the importance of this action, an additional indirect mechanism of Wnt/β-catenin antagonism in colon cancer has been proposed involving IL-1β, which will be reviewed in section 1α,25(OH)2D3 and Cytokines. Although 1,25(OH)2D3 inhibits β-catenin/TCF transcriptional activity in colon and other cancer cells, the upregulation of the Wnt/β-catenin pathway by either ligand-activated or unliganded VDR has been described in osteoblasts and keratinocytes, where it promotes bone formation and hair follicle differentiation, respectively (Larriba et al., 2013). However, the results reported in keratinocytes are controversial: while VDR enhances Wnt signaling through direct binding to Lymphocyte Enhancer-binding Factor (LEF)-1 independently of ligand and β-catenin (Luderer et al., 2011), ligand-activated VDR is believed to inhibit Wnt/β-catenin signaling (Bikle, 2011; Jiang et al., 2012).


Interaction of vitamin D with membrane-based signaling pathways.

Larriba MJ, González-Sancho JM, Bonilla F, Muñoz A - Front Physiol (2014)

Schematic representation of the multilevel crosstalk of 1α,25(OH)2D3 (1,25) with Wnt, Hedgehog, and Notch signaling pathways. For simplicity, only main components and regulators of the pathways are shown. Explanations, details, and references can be found in the text.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927071&req=5

Figure 1: Schematic representation of the multilevel crosstalk of 1α,25(OH)2D3 (1,25) with Wnt, Hedgehog, and Notch signaling pathways. For simplicity, only main components and regulators of the pathways are shown. Explanations, details, and references can be found in the text.
Mentions: Wnt factors activate several signaling pathways upon binding to different plasma membrane receptors: the canonical or Wnt/β-catenin and the non-canonical (planar polarity, Ca2+…) pathways (Clevers and Nusse, 2012). Activation of the Wnt/β-catenin pathway by mutation of APC or AXIN tumor suppressor genes or of CTNNB1/β-catenin oncogene together with changes in the expression of a number of regulatory genes (SFRPs, DICKKOPF (DKK)s…) is a hallmark of most colorectal cancers and of a variable proportion of several other malignancies (Clevers and Nusse, 2012). A series of studies report that 1α,25(OH)2D3 antagonizes Wnt/β-catenin signaling in colon cancer cells by several mechanisms: the reduction of transcriptionally active β-catenin/T-cell factor complexes, the induction of β-catenin relocation from the nucleus toward the adherens junctions structures at the plasma membrane, and the increase in the level of the Wnt inhibitor DKK-1 (Pálmer et al., 2001; Shah et al., 2006; Aguilera et al., 2007) (Figure 1). In this way, the pathway endpoint, i.e., the activation of β-catenin target genes, is attenuated by 1α,25(OH)2D3 (Pálmer et al., 2001). Emphasizing the importance of this action, an additional indirect mechanism of Wnt/β-catenin antagonism in colon cancer has been proposed involving IL-1β, which will be reviewed in section 1α,25(OH)2D3 and Cytokines. Although 1,25(OH)2D3 inhibits β-catenin/TCF transcriptional activity in colon and other cancer cells, the upregulation of the Wnt/β-catenin pathway by either ligand-activated or unliganded VDR has been described in osteoblasts and keratinocytes, where it promotes bone formation and hair follicle differentiation, respectively (Larriba et al., 2013). However, the results reported in keratinocytes are controversial: while VDR enhances Wnt signaling through direct binding to Lymphocyte Enhancer-binding Factor (LEF)-1 independently of ligand and β-catenin (Luderer et al., 2011), ligand-activated VDR is believed to inhibit Wnt/β-catenin signaling (Bikle, 2011; Jiang et al., 2012).

Bottom Line: Moreover, post-transcriptional and post-translational effects of 1α,25(OH)2D3 add to or overlap with its classical modulation of gene transcription rate.Therefore, we propose that future research in the vitamin D field should focus on the interplay between 1α,25(OH)2D3 and agents that act at the plasma membrane, and on the analysis of intercellular communication.Global analyses such as RNA-Seq, transcriptomic arrays, and genome-wide ChIP are expected to dissect the interactions at the gene and molecular levels.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid Madrid, Spain.

ABSTRACT
Many studies in different biological systems have revealed that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) modulates signaling pathways triggered at the plasma membrane by agents such as Wnt, transforming growth factor (TGF)-β, epidermal growth factor (EGF), and others. In addition, 1α,25(OH)2D3 may affect gene expression by paracrine mechanisms that involve the regulation of cytokine or growth factor secretion by neighboring cells. Moreover, post-transcriptional and post-translational effects of 1α,25(OH)2D3 add to or overlap with its classical modulation of gene transcription rate. Together, these findings show that vitamin D receptor (VDR) cannot be considered only as a nuclear-acting, ligand-modulated transcription factor that binds to and controls the transcription of target genes. Instead, available data support the view that much of the complex biological activity of 1α,25(OH)2D3 resides in its capacity to interact with membrane-based signaling pathways and to modulate the expression and secretion of paracrine factors. Therefore, we propose that future research in the vitamin D field should focus on the interplay between 1α,25(OH)2D3 and agents that act at the plasma membrane, and on the analysis of intercellular communication. Global analyses such as RNA-Seq, transcriptomic arrays, and genome-wide ChIP are expected to dissect the interactions at the gene and molecular levels.

No MeSH data available.


Related in: MedlinePlus