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B Activation and Suppresses Apoptosis Induced by TNF
* Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, and
Introgen Therapeutics, Houston, TX 77030
Melanoma differentiation-associated gene-7 (mda-7), also referred to as IL-24, is a novel growth regulatory cytokine that has been shown to regulate the immune system by inducing the expression of inflammatory cytokines, such as TNF, IL-1, and IL-6. Whether the induction of these cytokines by MDA-7 is mediated through activation of NF-
B or whether it regulates cytokine signaling is not known. In the present report we investigated the effect of MDA-7 on NF-B activation and on TNF-induced NF-B activation and apoptosis in human embryonic kidney 293 cells. Stable or transient transfection with mda-7 into 293 cells failed to activate NF-B. However, TNF-induced NF-B activation was significantly enhanced in mda-7-transfected cells, as indicated by DNA binding, p65 translocation, and NF-B-dependent reporter gene expression. Mda-7 transfection also potentiated NF-B reporter activation induced by TNF receptor-associated death domain and TNF receptor-associated factor-2. Cytoplasmic MDA-7 with deleted signal sequence was as effective as full-length MDA-7 in potentiating TNF-induced NF-B reporter activity. Secretion of MDA-7 was not required for the potentiation of TNF-induced NF-B activation. TNF-induced expression of the NF-B-regulated gene products cyclin D1 and cyclooxygenase-2, were significantly up-regulated by stable expression of MDA-7. Furthermore, MDA-7 expression abolished TNF-induced apoptosis, and suppression of NF-B by IB
kinase inhibitors enhanced apoptosis. Overall, our results indicate that stable or transient MDA-7 expression alone does not substantially activate NF-B, but potentiates TNF-induced NF-B activation and NF-B-regulated gene expression. Potentiation of NF-B survival signaling by MDA-7 inhibits TNF-mediated apoptosis.
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