CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island

Lapchak, Peter H.; Melter, Michael; Pal, Soumitro; Flaxenburg, Jesse A.; Geehan, Christopher; Frank, Markus H.; Mukhopadhyay, Debabrata; Briscoe, David M.

doi:10.1152/ajprenal.00070.2004

Cited by 11 publications

(16 citation statements)

References 70 publications

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“…Moreover, while the effect of TRAF1, -2, -3 and -5 was modest, TRAF6 knockdown resulted in a marked induction of basal levels of VEGF expression ( P <0.0001). Also, and consistent with our previously published studies [2,8,21,24], we found that the treatment of EC with sCD40L resulted in a 2-3-fold increase in VEGF transactivation. However, following activation, there was a greater increase in VEGF promoter activity in EC transfected with siRNAs to TRAF2 (approx.…”

Section: Resultssupporting

confidence: 93%

“…However, only a few studies have evaluated their expression and function in EC [23,30,31,32], and their role in angiogenesis has not been previously explored. CD40-induced responses in EC are potent to induce VEGF expression, VEGF-dependent EC proliferation in vitro and angiogenesis in vivo [2,3,8,21,24]. Furthermore, CD40-induced angiogenesis is associated with breast cancer growth and progression [4,5].…”

Section: Discussionmentioning

confidence: 99%

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TRAF6 inhibits proangiogenic signals in endothelial cells and regulates the expression of vascular endothelial growth factor

Bruneau

Datta

Flaxenburg

et al. 2012

Biochemical and Biophysical Research Communications

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TNF-family molecules induce the expression Vascular Endothelial Growth Factor (VEGF) in endothelial cells (EC) and elicit signaling responses that result in angiogenesis. However, the role of TNF-receptor associated factors (TRAFs) as upstream regulators of VEGF expression or as mediators of angiogenesis is not known. In this study, HUVEC were cotransfected with a full-length VEGF promoter-luciferase construct and siRNAs to either TRAF 1–6, and promoter activity was measured. Paradoxically, rather than inhibiting VEGF expression, we found that knockdown of TRAF6 resulted in a 4–6 fold increase in basal VEGF promoter activity compared to control siRNA-transfected EC (P<0.0001). In addition, knockdown of TRAF 1, -2, -3 or -5 resulted in a slight increase or no change in VEGF promoter activation. Using [3H]thymidine incorporation assays as well as the in vitro wound healing assay, we also found that basal rates of EC proliferation and migration were increased following TRAF6 knockdown; and this response was inhibited by the addition of a blocking anti-VEGF antibody into cell cultures. Using a limited protein array to gain insight into TRAF6-dependent intermediary signaling responses, we observed that TRAF6 knockdown resulted in an increase in the activity of Src family kinases. In addition, we found that treatment with AZD-0530, a pharmacological Src inhibitor, reduced the regulatory effect of TRAF6 knockdown on VEGF promoter activity. Collectively, these findings define a novel pro-angiogenic signaling response in EC that is regulated by TRAF6.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

TRAF6 inhibits proangiogenic signals in endothelial cells and regulates the expression of vascular endothelial growth factor

Bruneau

Datta

Flaxenburg

et al. 2012

Biochemical and Biophysical Research Communications

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“…In contrast, the VEGF promoter was not methylated as analyzed by MSP. The human umbilical vascular endothelial cell, which does not express VEGF and has been reported to involve promoter methylation for VEGF transcriptional regulation, was used as control (25).…”

Section: Methylation Status Of Plgf Promoter In Lung and Colon Carcinmentioning

confidence: 99%

Down-Regulation of Placenta Growth Factor by Promoter Hypermethylation in Human Lung and Colon Carcinoma

Jain²

2007

Molecular Cancer Research

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“…Cell suspensions were incubated with primary antibody, washed, and incubated with a secondary FITC-conjugated antibody at 4°C for 30 min as described (14). The stained cells were washed and fixed in 1% paraformaldehyde and analyzed by FACScan (Becton-Dickinson, Oxnard, CA).…”

Section: Flow Cytometrymentioning

confidence: 99%

Cd40

Laxmanan

Datta²,

Geehan³

et al. 2005

Journal of the American Society of Nephrology

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Infiltration of immune cells into the renal interstitium is characteristic of chronic inflammatory kidney diseases. CD4؉ T cells and platelets express CD40 ligand (CD40L) and are reported to mediate proinflammatory events in renal proximal tubular epithelial cells (RPTEC) via interaction with CD40. In other cell types, CD40 signals can also induce protective genes. Here, human RPTEC were treated with sCD40L to ligate CD40, and a significant increase in the generation of proinflammatory reactive oxygen species was found; however, CD40-activated cells did not undergo apoptosis. This suggests that CD40 signals may simultaneously induce antiapoptotic genes for cytoprotection of RPTEC. Heme oxygenase-1 (HO-1) expressed in RPTEC serves as a protective gene, but it is not known whether it is regulated by CD40. Next, RPTEC were transiently transfected with a full-length HO-1 promoter-luciferase construct and were treated with sCD40L. CD40 ligation was found to significantly increase HO-1 promoter activity. By electrophoretic mobility shift assay, it was confirmed that CD40 signaling induced the transcriptional activation of HO-1 through the binding of NF-B to its promoter. By Western blot analysis, a marked increase in HO-1 protein expression following CD40 ligation was also found. These observations are of clinical significance because it was found that CD40 and HO-1 are induced in expression in vivo in inflamed rejecting kidney biopsies and co-expressed in renal tubules. Therefore, ligation of CD40 in RPTEC promotes both inflammatory and anti-inflammatory processes.Regulating the balance between these two events may be of importance in the prevention of tubular injury associated with renal disease.

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CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island

Abstract: . CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island. Am J Physiol

Cited by 11 publications

References 70 publications

TRAF6 inhibits proangiogenic signals in endothelial cells and regulates the expression of vascular endothelial growth factor

TRAF6 inhibits proangiogenic signals in endothelial cells and regulates the expression of vascular endothelial growth factor

Down-Regulation of Placenta Growth Factor by Promoter Hypermethylation in Human Lung and Colon Carcinoma

Cd40

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