P22PRG1/IEX-1 is a putative NF-kappaB target gene implicated in the regulation of cellular viability. Here, we show that in HeLa cells TNFalpha induces expression of p22PRG1/IEX-1 in an NF-kappaB dependent fashion. Blockade of NF-kappaB activation by various NF-kappaB inhibitors abolished TNFalpha-induced p22PRG1/IEX-1 expression and increased the sensitivity to apoptosis induced by TNFalpha, an activating Fas-antibody or the anti-cancer drug etoposide. Surprisingly, ectopic expression of p22PRG1/IEX-1 in HeLa cells transfected with an inducible p22PRG1/IEX-1-expression vector augments the susceptibility to apoptosis initiated by death-receptor ligands or by etoposide. In addition, p22PRG1/IEX-1 expressing HeLa cells exhibit an accelerated progression through the cell cycle. Transfection of an antisense hammerhead ribozyme targeted to p22PRG1/IEX-1 reduced the speed in cell cycle progression and decreased the apoptotic response to death ligands. Our data demonstrate that p22PRG1/IEX-1 is specifically induced during NF-kappaB activation, but this seems not to be related to the anti-apoptotic actions of NF-kappaB. Instead, NF-kappaB dependent recruitment of p22PRG1/IEX-1 might be related to a modulation in the cell cycle, and hereby, p22PRG1/IEX-1 may accelerate cell growth on the one hand, but may trigger apoptosis on the other. Oncogene (2001) 20, 69 - 76.
Immediate early gene X1 (IEX-1) represents a stress response gene involved in growth control and modulation of apoptosis. Here, we report a detailed analysis of IEX-1 with respect to its intracellular localization. By means of confocal laser scanning microscopy, a green fluorescent protein-IEX-1 fusion protein transfected into HeLa cells, as well as endogenous IEX-1, could be detected in distinct subnuclear structures. This particular subnuclear localization of IEX-1 was not observed with a green fluorescent protein-IEX-1 fusion protein lacking a putative nuclear localization sequence, along with a decreased effect on apoptosis. Double immunofluorescence staining revealed a partial co-localization of endogenous promyelocytic leukemia protein (PML) and IEX-1 in these subnuclear structures. Nuclear localization of IEX-1 is also enhanced upon treatment of cells with leptomycin B, an inhibitor of the nuclear exporter CRM1. These observations indicate that IEX-1 is specifically shuttled to and from the nucleus. Overexpression experiments using PML isoforms III and IV revealed distinct intranuclear interaction of IEX-1 and PML. Coprecipitation experiments showed physical interaction between IEX-1 and PML. The close structural relation of IEX-1-containing nuclear subdomains and PML nuclear bodies suggests a function of IEX-1 related to the multiple functions of these unique subnuclear regions, particularly during stress response and growth control.
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