Expression of the NF-kappa B target gene IEX-1 (p22/PRG1) does not prevent cell death but instead triggers apoptosis in Hela cells.
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.
Arlt
A
A
Laboratory of Molecular Gastroenterology, First Department of Medicine, University of Kiel, Schittenhelmstr. 12, D-24105 Kiel, Germany.
Grobe
O
O
Sieke
A
A
Kruse
M L
ML
Fölsch
U R
UR
Schmidt
W E
WE
Schäfer
H
H
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D005822:Genetic Vectors / Q000378:metabolism; D005912:Gliotoxin / Q000494:pharmacology; D006367:HeLa Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009363:Neoplasm Proteins; D016337:RNA, Catalytic / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology; D013752:Tetracycline / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C099815:IER3 protein, human; D017874:Immediate-Early Proteins; D007166:Immunosuppressive Agents; D007976:Leupeptins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D016337:RNA, Catalytic; D014409:Tumor Necrosis Factor-alpha; C116501:acetyl-leucinal-leucinal-normethional; D012460:Sulfasalazine; D005912:Gliotoxin; D013752:Tetracycline; D007930:Leucine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde