Expression of endoglin and the activin receptor-like kinase 1 in skin suggests a role for these receptors in normal skin function and skin tumorigenesis

Beger, B.; Robertson, Katherine; Evans, Alan; Grant, A.; Berg, Jonathan

doi:10.1111/j.1365-2133.2005.07043.x

Cited by 8 publications

(7 citation statements)

References 7 publications

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“…Consistent with this, previous reports of CD105 expression in human and murine skin in situ demonstrate expression in keratinocytes, activated endothelial cells only, and activated macrophages and monocytes (36) but not in stromal cells of the dermis. (37,38). Although CD105 has been reported to be expressed by fibroblastic skin-derived dermal cells, many of these studies were performed on long-term-cultured cells (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

A role for pericytes as microenvironmental regulators of human skin tissue regeneration

Paquet-Fifield¹,

Schlüter²,

Li³

et al. 2009

J. Clin. Invest.

149

173

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The cellular and molecular microenvironment of epithelial stem and progenitor cells is poorly characterized despite well-documented roles in homeostatic tissue renewal, wound healing, and cancer progression. Here, we demonstrate that, in organotypic cocultures, dermal pericytes substantially enhanced the intrinsically low tissue-regenerative capacity of human epidermal cells that have committed to differentiate and that this enhancement was independent of angiogenesis. We used microarray analysis to identify genes expressed by human dermal pericytes that could potentially promote epidermal regeneration. Using this approach, we identified as a candidate the gene LAMA5, which encodes laminin α5, a subunit of the ECM component laminin-511/521 (LM-511/521). LAMA5 was of particular interest as we had previously shown that it promotes skin regeneration both in vitro and in vivo. Analysis using immunogold localization revealed that pericytes synthesized and secreted LAMA5 in human skin. Consistent with this observation, coculture with pericytes enhanced LM-511/521 deposition in the dermal-epidermal junction of organotypic cultures. We further showed that skin pericytes could also act as mesenchymal stem cells, exhibiting the capacity to differentiate into bone, fat, and cartilage lineages in vitro. This study suggests that pericytes represent a potent stem cell population in the skin that is capable of modifying the ECM microenvironment and promoting epidermal tissue renewal from non-stem cells, a previously unsuspected role for pericytes.

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Section: Discussionmentioning

confidence: 99%

A role for pericytes as microenvironmental regulators of human skin tissue regeneration

Paquet-Fifield¹,

Schlüter²,

Li³

et al. 2009

J. Clin. Invest.

149

173

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“…During liver fibrosis, ligand-activated ALK1 activates the target gene Id1 through the Smad1 pathway, thereby inducing HSCs to differentiate into fibroblasts, which produce ECM proteins [ 39 , 40 ]. In other fibrotic diseases, such as scleroderma, research has demonstrated an abnormal overexpression of ALK1 and its associated activated proteins [ 41 , 42 ].…”

Section: Relationship Between Activin Receptor-like Kinase 1 (Alk1mentioning

confidence: 99%

Potential Roles of BMP9 in Liver Fibrosis

2014

IJMS

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Liver fibrosis is a common phenomenon that is associated with several pathologies and is characterized by excessive extracellular matrix deposition that leads to progressive liver dysfunction. Bone morphogenetic protein 9 (BMP9) is the most recently discovered member of the BMP family. BMP9 bound with high affinity to activin receptor-like kinase 1 (ALK1) and endoglin in non-parenchymal liver cells. In addition, BMP9 activated Smad1/Smad5/Smad8 and induced the expression of the target genes inhibitor of differentiation 1 (Id1), hepcidin, Snail and the co-receptor endoglin in liver cells. Although the role of BMP9 in liver fibrosis is currently poorly understood, the presence of BMP9-activated proteins and its target genes have been reported to be associated with liver fibrosis development. This review summarizes the indirect connection between BMP9 and liver fibrosis, with a focus on the BMP9 signaling pathway members ALK1, endoglin, Id1, hepcidin and Snail. The observations on the role of BMP9 in regulating liver fibrosis may help in understanding the pathology mechanisms of liver disease. Furthermore, BMP9 could be served as a potent biomarker and the target of potential therapeutic drugs to treat hepatocytes fibrosis.

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“…ALK1 (Activin receptor-Like Kinase 1) is a transmembrane type I receptor of the Transforming Growth Factor-β (TGF-β) superfamily of ligands, mainly found in endothelial cells. Its expression has been reported not only in highly vascularized tissues including lung, placenta, and heart [ 1 , 2 ], but also at specific sites of epithelial-mesenchymal interactions [ 3 ], and in other cell types such as monocytes [ 4 ], microglia [ 5 ], skin fibroblasts [ 6 ], stellate hepatic cells [ 7 ], chondrocytes [ 8 ], neural crest stem cells [ 9 ] and more recently myoblasts [ 10 ]. Nonetheless, most studies to date suggest that its major roles are related to the endothelial specific expression pattern.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the human Activin-A receptor type II-like kinase 1 (ACVRL1) promoter and its regulation by Sp1

et al. 2010

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BackgroundActivin receptor-like kinase 1 (ALK1) is a Transforming Growth Factor-β (TGF-β) receptor type I, mainly expressed in endothelial cells that plays a pivotal role in vascular remodelling and angiogenesis. Mutations in the ALK1 gene (ACVRL1) give rise to Hereditary Haemorrhagic Telangiectasia, a dominant autosomal vascular dysplasia caused by a haploinsufficiency mechanism. In spite of its patho-physiological relevance, little is known about the transcriptional regulation of ACVRL1. Here, we have studied the different origins of ACVRL1 transcription, we have analyzed in silico its 5'-proximal promoter sequence and we have characterized the role of Sp1 in the transcriptional regulation of ACVRL1.ResultsWe have performed a 5'Rapid Amplification of cDNA Ends (5'RACE) of ACVRL1 transcripts, finding two new transcriptional origins, upstream of the one previously described, that give rise to a new exon undiscovered to date. The 5'-proximal promoter region of ACVRL1 (-1,035/+210) was analyzed in silico, finding that it lacks TATA/CAAT boxes, but contains a remarkably high number of GC-rich Sp1 consensus sites. In cells lacking Sp1, ACVRL1 promoter reporters did not present any significant transcriptional activity, whereas increasing concentrations of Sp1 triggered a dose-dependent stimulation of its transcription. Moreover, silencing Sp1 in HEK293T cells resulted in a marked decrease of ACVRL1 transcriptional activity. Chromatin immunoprecipitation assays demonstrated multiple Sp1 binding sites along the proximal promoter region of ACVRL1 in endothelial cells. Furthermore, demethylation of CpG islands, led to an increase in ACVRL1 transcription, whereas in vitro hypermethylation resulted in the abolishment of Sp1-dependent transcriptional activation of ACVRL1.ConclusionsOur results describe two new transcriptional start sites in ACVRL1 gene, and indicate that Sp1 is a key regulator of ACVRL1 transcription, providing new insights into the molecular mechanisms that contribute to the expression of ACVRL1 gene. Moreover, our data show that the methylation status of CpG islands markedly modulates the Sp1 regulation of ACVRL1 gene transcriptional activity.

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Expression of endoglin and the activin receptor-like kinase 1 in skin suggests a role for these receptors in normal skin function and skin tumorigenesis

Cited by 8 publications

References 7 publications

A role for pericytes as microenvironmental regulators of human skin tissue regeneration

A role for pericytes as microenvironmental regulators of human skin tissue regeneration

Potential Roles of BMP9 in Liver Fibrosis

Characterization of the human Activin-A receptor type II-like kinase 1 (ACVRL1) promoter and its regulation by Sp1

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