Tumor necrosis factor-α induces the expression of DR6, a member of the TNF receptor family, through activation of NF-κB

Abstract

The tumor necrosis factor (TNF) receptor family are ligand-regulated transmembrane proteins that mediate apoptosis as well as activation of the transcription factor NF-kB. Exogenous expression of DR6, a recently identi®ed member of the TNF receptor family, induced apoptosis in untransformed or tumor-derived cells and the apoptotic function of DR6 was inhibited by coexpression of Bcl-2, Bcl-x L or the inhibitor-of-apoptosis (IAP) family member, survivin. Expression of a dominant negative mutant of FADD failed to protect from DR6-mediated apoptosis indicating that unlike TNFR1 and Fas, DR6 induced apoptosis via a FADDindependent mechanism. Despite the ability of exogenous DR6 expression to induce apoptosis, DR6 mRNA and protein were found to be elevated in prostate tumor cell lines and in advanced stages of prostate cancer. Analysis of several anti-apoptotic proteins revealed that Bcl-x L levels and serine 32 phosphorylation of IkB, the natural inhibitor of NF-kB, were similarly elevated in cells expressing high levels of DR6, suggesting that NF-kBregulated survival proteins may protect from DR6-induced apoptosis and that DR6 is a target of NF-kB regulation. Treatment of LnCAP cells with TNF-a resulted in increases in both DR6 mRNA and protein levels, and this induction was suppressed by inhibitors of NF-kB. Similarly, treatment of cells expressing high levels of DR6 with indomethacin and ibuprofen, compounds also known to perturb NF-kB function, resulted in a dose-dependent decrease in DR6 protein and mRNA levels. These results demonstrate that TNF-a signaling induces the expression of a member of its own receptor family through activation of NF-kB. Oncogene (2001) 20, 7965 ± 7975.

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

“…Recently, nitric oxide-induced activation of p38 was implicated in triggering NF-kB-mediated expression of p53, leading to upregulation of the proapoptotic Bcl-2 family member Bax, just as cyanide-induced activation of NF-kB resulted in activation of the proapoptotic Bcl-xS and Bax proteins (Kim et al, 2002b;Shou et al, 2002). Other examples include NFkB-dependent activation of DR ligand TRAIL and TNF receptor family member DR6 (Baetu et al, 2001;Kasof et al, 2001;Rivera-Walsh et al, 2001;Siegmund et al, 2001). In one study, c-Rel induced expression of TRAIL receptors DR4 (TRAIL-R1), DR5 (TRAIL-R2) and the proapoptotic Bcl-2 family member Bcl-xS to sensitize cells to TRAIL-induced apoptosis .…”

Radiation-triggered Tumor Necrosis Factor (TNF) α-NFκB Cross-signaling Favors Survival Advantage in Human Neuroblastoma Cells

“…To that extent, blocking NFB has been demonstrated to sensitize cancer cells to TNF␣-induced killing (21,41). Similarly, studies, both in vitro and in vivo, have demonstrated that pretreatment of cells with TNF␣ resulted in increased NFB activation (42,43). Recently, it has been demonstrated that endogenous production of TNF␣ is a potent trigger of NFB activation by IR.…”

In vitro antitumor effects of two novel oligostilbenes, cis- and trans-suffruticosol D, isolated from Paeonia suffruticosa seeds

“…p27, the cyclin-dependent kinase inhibitor, controls the cell cycle progression at G1 by preventing the activation of cyclin E-Cdk2 or cyclin D1-Cdk4 complexes (36,37). DR6, also known as TNFRSF21, is a member of the death receptor family, which induces apoptosis in mammalian cells and its apoptotic function is inhibited by survivin (38). Downregulation of XIAP, survivin, Hsp60 and Hsp70, as well as upregulation of BID, DR6 and p27 by cis-and transsuffruticosol D at least partially contribute to the apoptotic effect of cis-and trans-suffruticosol D.…”