Stimulation of Id1 Expression by Bone Morphogenetic Protein Is Sufficient and Necessary for Bone Morphogenetic Protein–Induced Activation of Endothelial Cells

Valdimarsdóttir, Guðrún; Goumans, Marie–José; Rosendahl, Alexander; Brugman, Martijn H.; Itoh, Susumu; Lebrin, Franck; Sideras, Paschalis; Dijke, Peter ten

doi:10.1161/01.cir.0000033830.36431.46

Cited by 276 publications

(229 citation statements)

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“…Up-regulation of ID genes is an important event in this response, and has been demonstrated to be dependent on Smad phosphorylation [8]. We used a reporter assay to demonstrate this also in Jurkat TAg cells.…”

Section: Discussionmentioning

confidence: 91%

“…The dependency on Id1 up-regulation is in accordance with studies of BMP effects in other cellular systems. In endothelial cells it has been shown that BMP-6 stimulated migration and tube formation via Id1 up-regulation [8]. The functional effects of BMP-2 in a lung cancer cell line were also related to Smad1-dependent up-regulation of Id1 [6].…”

Section: Discussionmentioning

confidence: 97%

“…Several studies have pointed toward members of the inhibitor of DNA binding (Id) protein family, a class of helix-loop-helix (HLH) proteins, as important targets for BMP signalling [5][6][7][8]. HLH proteins act as transcriptional regulators and are essential factors for lymphoid development and function [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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Bone morphogenetic proteins (BMP) are multifunctional cytokines that belong to the TGF-b superfamily. BMP have been shown to regulate haematopoietic stem cells, B lymphopoiesis and early thymocyte differentiation. In the present study we explored the role of BMP-6 in Jurkat TAg cells. BMP-6 rapidly induced phosphorylation of Smad1/5/8, p38 and ERK1/2, followed by a potent up-regulation of ID1, ID2 and ID3. ID1 and ID3 were also induced at the protein level. Genome-wide expression profiling of cells treated with BMP-6 compared to medium confirmed that ID1-ID3 were target genes of BMP-6 together with Noggin and Smad6. Furthermore, several genes involved in transcriptional regulation were also identified, including NFKBIA, HEY1, DLX2, KLF10 and early growth response 1. Stimulation with BMP-6 exerted an antiproliferative effect that was counteracted by inhibitor of DNA binding (Id)1 siRNA, indicating that Id1 is an important downstream mediator in Jurkat TAg cells. A subset of CD4 + T cells were found to express the BMP receptors Alk-2 and Alk-3 (type I), in addition to BMPRII (type II). BMP-6 also induced phosphorylation of Smad1/5/8, followed by transcriptional increase in ID1-ID3 mRNA expression. However, we did not observe significant changes in Id protein expression in CD4 + T cells. Altogether, the data indicate a role for BMP-6 in human T lineage cells.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 97%

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Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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“…At the same time, BMP6 significantly inhibits in vitro tubule formation by human endothelial cells down to the level of the negative control (Figure 4), giving a further possible link with BM angiogenesis and thus prognosis. These were surprising results, as BMP6 has been described as an agonist for endothelial cell migration and tube formation in vitro (Valdimarsdottir et al, 2002) using adenoviral-transfected BMP-receptor-expressing mouse embryonic endothelial cells and bovine aortic endothelial cells. Differences might be explained by speciesdependent action of BMP6 and/or receptor expression or a difference in action of BMP6 on embryonic vs adult endothelial cells.…”

Section: Biological Implicationsmentioning

confidence: 94%

“…In prostate (Hamdy et al, 1997;Haudenschild et al, 2004;Dai et al, 2005) and breast cancer (Clement et al, 1999), BMP6 expression promotes tumor progression and metastasis. BMP6 has been described to be a proangiogenic factor in terms of endothelial cell migration and tube formation in vitro (Valdimarsdottir et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Bone morphogenic protein 6: a member of a novel class of prognostic factors expressed by normal and malignant plasma cells inhibiting proliferation and angiogenesis

et al. 2009

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Pathogenesis of multiple myeloma is associated with an aberrant expression of pro-proliferative, pro-angiogenic and bone-metabolism-modifying factors by malignant plasma cells. Given the frequently long time span from diagnosis of early-stage plasma cell dyscrasias to overt myeloma and the mostly low proliferation rate of malignant plasma cells, we hypothesize these to similarly express a novel class of inhibitory factors of potential prognostic relevance. Bone morphogenic proteins (BMPs) represent possible candidates as they inhibit proliferation, stimulate bone formation and have an effect on the survival of cancer patients. We assessed the expression of BMPs and their receptors by Affymetrix DNA microarrays (n ¼ 779) including CD138-purified primary myeloma cell samples (n ¼ 635) of previously untreated patients. BMP6 is the only BMP expressed by malignant and normal plasma cells. Its expression is significantly lower in proliferating myeloma cells, myeloma cell lines or plasmablasts. BMP6 significantly inhibits the proliferation of myeloma cell lines, survival of primary myeloma cells and in vitro angiogenesis. A high BMP6 expression in primary myeloma cell samples delineates significantly superior overall survival for patients undergoing high-dose chemotherapy independent of conventional prognostic factors (International Staging System (ISS) stage, b 2 microglobulin).

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Regulation of the Angiogenesis of Acquired Middle Ear Cholesteatomas by Inhibitor of DNA Binding Transcription Factor

Fukudome

Wang

Hamajima

et al. 2013

JAMA Otolaryngol Head Neck Surg

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Importance:The aggressive growth of cholesteatoma in the middle ear involves the angiogenesis of the cholesteatomal perimatrix. However, which transcription factor is involved in this process remains unclear.Objective: To identify a transcription factor that supports the aggressive growth of cholesteatoma by controlling the angiogenesis of cholesteatoma in the middle ear milieu.Design: We used clinical specimens for the profiling of angiogenic factors and their regulatory transcription factors in cholesteatoma. Human skin keratinocytes and endothelial cells were used for evaluation of the effects of candidate transcription factor on the angiogenic factor regulation and endothelial cell proliferation.Setting: University departments of otolaryngologyhead and neck surgery.Participants: Eight clinical cholesteatomal and 8 control specimens were used for cellular and molecular biologic evaluation. An additional 8 cholesteatomal and 8 aural skin specimens were used for microarray studies. Main Outcome Measures:The expression of vascular endothelial growth factor, interleukin 8, and cyclooxygenase 2 as measured by means of immunohistochemistry and molecular biologic methods.Results: Human aural cholesteatomal specimens were rich in the expression of angiogenic factors such as vascular endothelial growth factor in the cholesteatomal matrix and perimatrix, accompanied by the transcription factor inhibitor of DNA binding (Id1). We found Id1 to be an essential regulator of vascular endothelial growth factor. In addition, potent angiogenic factors, including interleukin 8 and cyclooxygenase 2, were regulated by Id1 via different molecular mechanisms. Conclusions and Relevance:The transcription factor Id1 controls the angiogenesis of cholesteatoma through the regulation of vascular endothelial growth factor, interleukin 8, and cyclooxygenase 2, which are responsible for the angiogenesis of cholesteatoma. Id1 may serve as a good target for the treatment of cholesteatomal progression in the middle ear milieu.

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Stimulation of Id1 Expression by Bone Morphogenetic Protein Is Sufficient and Necessary for Bone Morphogenetic Protein–Induced Activation of Endothelial Cells

Abstract: The BMP/Smad pathway can potently activate the endothelium. Id1 expression is strongly induced by BMP in ECs. Ectopic expression of Id1 induces EC migration and tube formation. Moreover, Id1 played a critical role in mediating BMP-induced EC migration.

Cited by 276 publications

References 21 publications

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

Bone morphogenic protein 6: a member of a novel class of prognostic factors expressed by normal and malignant plasma cells inhibiting proliferation and angiogenesis

Regulation of the Angiogenesis of Acquired Middle Ear Cholesteatomas by Inhibitor of DNA Binding Transcription Factor

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