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VEGI, a new member of the TNF family activates Nuclear Factor-κB and c-Jun N-terminal kinase and modulates cell growth

Abstract

Recently a new member of the human tumor necrosis factor (TNF) family named as VEGI was reported. However, very little is known about the biological activities displayed by this cytokine. In this report, we show that in myeloid cells VEGI activated the transcription factor κB (NF-κB) as determined by the electrophoretic mobility shift assay, induced degradation of IκBα, and nuclear translocation of p65 subunit of NF-κB. VEGI also activated NF-κB-dependent reporter gene expression. In addition, VEGI activated c-Jun N-terminal kinase. When examined for growth modulatory effects, VEGI inhibited the proliferation of breast carcinoma (MCF-7), epithelial (HeLa), and myeloid (U-937 and ML-1a) tumor cells; and activated caspase-3 leading to PARP cleavage. VEGI-induced cytotoxicity was potentiated by inhibitors of protein synthesis. VEGI also induced proliferation of normal human foreskin fibroblast cells. The activity of VEGI could neither be neutralized by antibodies against TNF, nor could it compete with TNF binding, indicating that the activity of VEGI is not due to TNF and it binds to a distinct receptor. These results suggest that VEGI, a new member of the TNF family, has a signaling pathway similar to TNF and is most likely a multifunctional cytokine.

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Abbreviations

TNF:

tumor necrosis factor

TWEAK:

a weak homologue of TNF

TNANK:

TNF homologue that activates NF-κB, JNK and apoptosis

NF-κB:

nuclear transcription factor-κB

IκB:

inhibitory subunit of NF-κB

IL:

interleukin

EMSA:

electrophoretic mobility shift assay

MAPK:

mitogen-activated protein kinase

VEGI:

vascular endothelial cell-derived growth inhibitor

PARP:

poly(A)+ (ADP-ribose) polymerase

DR3L:

death receptor-3 ligand

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This research was supported by The Clayton Foundation.

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Haridas, V., Shrivastava, A., Su, J. et al. VEGI, a new member of the TNF family activates Nuclear Factor-κB and c-Jun N-terminal kinase and modulates cell growth. Oncogene 18, 6496–6504 (1999). https://doi.org/10.1038/sj.onc.1203059

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