Human T-cell leukemia virus type I Tax-protein-mediated activation of NF-kappa B from p100 (NF-kappa B2)-inhibited cytoplasmic reservoirs.

Abstract

The human T-cell leukemia virus type I Tax protein transforms T cells through induced expression of many cellular genes, including those encoding the growth-related proteins interleukin 2 and the a chain of its receptor. Induction of these genes is mediated, at least in part, through Taxdependent posttranslational activation of NF-cB, typically heterodimers of p50 (NF-ocB1) and p65 (RelA). The preexisting NF-KB proteins are retained in the cytoplasm of cells by association with inhibitory ankyrin-motif-containing I#cB proteins, primarily I&B-a but also including the precursor proteins p105 (NF-#cBl) and plOO (NF-cB2). Here we demonstrate the existence of a previously undescribed multimeric cytoplasmic complex in which NF-,cB dimers are associated with the plOO inhibitor in a manner dependent on the precursor protein's ankyrin domain. We also demonstrate an antagonistic effect of the Tax protein on the cytoplasmic sequestration function of plOO; this in turn leads to nuclear translocation of NF-KB dimers liberated from multimeric complexes. Tax may exert these effects through the physical association with plOO. Tax also relieves the plOO-mediated inhibition of DNA binding by p50-p65 heterodimers in vitro. The results demonstrate a mechanism by which Tax may activate NF-KB in T cells.

Transcriptional regulatory effects of lymphoma-associated NFKB2/lyt10 protooncogenes

“…A model invoking loss of IkB-like activity would also be consistent with older reports that inhibition of IkBa by antisense approaches resulted in transformation of NIH3T3 cells (Beauparlant et al, 1994), and with reports of IkBa mutations in patients with Hodgkin's disease (Cabannes et al, 1999;Krappmann et al, 1999;Wood et al, 1998). This model is also reminiscent of one reported mechanism by which HTLV-1 Tax leads to increased NF-kB activity (Kanno et al, 1994). In this model, Tax induces disruption of p100-containing complexes in the cytoplasm of T cells, leading to constitutive NF-kB activation.…”

Regulation of NF-κB activity by IκB-related proteins in adenocarcinoma cells

“…The HTLV-1 Tax protein was the only agent we tested that could induce a signi®cant NF-kB transcriptional activity in p100-expressing cells, but Tax dissociated the NF-kB/p100 complexes without inducing p100 processing (Kanno et al, 1994). In other words, our experiments so far failed to identify the agents that could trigger p100 phosphorylation and cleavage.…”

“…It acts through several mechanisms including binding to p65 and p105, inactivation of IkBa or IkB-b and dissociation of the p100/NF-kB complexes (Kanno et al, 1994;Hiscott et al, 1995;Good and Sun, 1996;McKinsey et al, 1996;Rousset et al, 1996). We therefore investigated whether Tax could induce NF-kB-dependent transcription in adenocarcinoma cells.…”

“…The 3xNF-kB(pIC)-tk-LUC plasmid reporter was kindly provided by Dr B van der Burg (Hubrecht Laboratory, Utrecht, Netherlands). The expression vector PMT2T-Tax was previously described (Kanno et al, 1994). The expression vector pCMV-CD20 was provided by Dr J Koh (MGH Cancer Center, Charlestown, MA, USA).…”

“…p100 and p105 are able to heterodimerize with other NF-kB proteins and their ankyrin repeat domain inhibits nuclear translocation of such dimers. However, it has also been demonstrated that p100 can form trimeric cytoplasmic complexes with p50/p65 or with p50/RelB (Kanno et al, 1994;Dejardin et al, 1995Dejardin et al, , 1998. Despite reports showing p100 cleavage after phorbol ester stimulation in HeLa cells and p105 partial degradation by the proteasome pathway, little is known on the regulation of p100 or p105 processing in response to NF-kB-activating stimuli (Fan and Maniatis, 1991;Mercurio et al, 1993;Palombella et al, 1994).…”