Signaling pathway underlying the up-regulatory effect of TNF-alpha on the Na(+)/K(+) ATPase in HepG2 cells.
The activity of the Na(+)/K(+) ATPase was shown to be reduced during apoptosis and enhanced during cell proliferation. This work investigated whether TNF-alpha exerts also opposite effects on the Na(+)/K(+) ATPase in HepG2 cells and whether these effects are time-dependent. A time response study demonstrated that the activity and protein expression of the ATPase are decreased at 1h and increased at 4, 6 and 8h. This work focused on the up-regulatory 4h-response. TNF-alpha was shown to exert a stimulatory effect on cJNK and NF-kappaB and an inhibitory effect on caspases which, in the basal state, down-regulate the ATPase. The cytokine was found to target the caspases by activating JNK which in turn activates NF-kappaB. The activated transcription factor inhibits the caspases and frees the ATPase from their inhibitory action leading thus to its up-regulation.
Kassardjian
Ari
A
Department of Biology, American University of Beirut, Lebanon.
Dakroub
Zeina
Z
Zein
Ola El
OE
Kreydiyyeh
Sawsan Ibrahim
SI
D000590:Amino Acid Chloromethyl Ketones; D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects*
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D000254:Sodium-Potassium-Exchanging ATPase