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Pro-apoptotic role of casein Kinase 2 is mediated by a JNK signaling cascade


, : Pro-apoptotic role of casein Kinase 2 is mediated by a JNK signaling cascade. Hepatology 38(4 Suppl 1): 241A, October

The tetrameric enzyme Protein Kinase CK2 plays a significant role in the regulation of cell proliferation, malignant transformation and apoptosis. The catalytic alpha-subunit of the enzyme is known to exist in three isoforms, CK2alpha, CK2alpha' and the recently described CK2alpha", predominately located in the nuclear matrix of hepatocytes. Preliminary studies suggested that CK2alpha" plays a pivotal role in the induction of cell death. The AIM of the present study was to determine the mechanism whereby CK2alpha" regulates hepatocellular apoptosis. METHODS and RESULTS: When compared to wildtype (wt) HuH-7 cells, the CK2alpha" (-/-) Trf1 mutant cell line was resistant to apoptosis induced by a variety of cell death stimuli as determined by the MTT assay. By 90 h post-infection with dengue virus (DEN), 85-90% of the wt-HuH-7 cells had undergone cell death, in comparison to only 6% of Trf1 cells. After TNF treatment, 80% of wt-HuH-7 cells died within 48 h, but death in Trf1 cells was less than 10%. For other death stimuli, the reduction in cell death between wt-HuH-7 and Trf1 ranged from 75% for menadione, 62% for okadaic acid, 55% for H2O2, 50% for UV-light, to 43% for acetaminophen. The resistant phenotype was reverted by stable transfection of Trf1 cells with recombinant CK2alpha", which re-sensitized Trf1 cells to death induced by DEN, TNF and UV. Flowcytometric measurement of DNA hypoploidy revealed that DEN and TNF induced DNA fragmentation indicating that apoptosis was the predominant cause of cell death. Immunoblot analysis revealed that DEN infection did not induce caspase-3 or -8 activation in either cell line. In contrast, TNF treatment induced caspase activation in wt-HuH-7 with no effect in Trf1 cells. This differential response was confirmed by the selective inhibition of TNF induced apoptosis in wt-HuH-7 by the pan-caspase inhibitor Z-VAD-FMK and the caspase-3 inhibitor DEVD-CHO, while DEN induced cell death was unaffected. Mitochondrial permeability as indicated by the release of cytochrome c occurs upstream of caspase activation in different death pathways. Immunoblot analysis showed that DEN infection resulted in equal increases in cytoplasmic cytochrome c levels in both wt-HuH-7 and Trf1, as opposed to TNF, which had no effect. As CK2 has several potential links to NF-kappaB, induction of this pathway by DEN infection and TNF treatment was assessed either by the phosphorylation of IkappaB or by a luciferase assay of NF-kappaB transactivation. TNF induced equal activation of NF-kappaB in both cell lines. DEN infection did not result in NF-kappaB activation in either cell line. Evaluation of JNK related pathways involved in death signaling revealed a dramatic deficiency of c-Jun phosphorylation after stimulation with DEN or TNF in Trf1 cells without affecting the absolute concentration of either JNK or c-Jun. To test the significance of c-Jun in HuH-7 death signaling, cells were pre-infected with a dominant negative c-Jun expressing adenovirus. TNF induced cell death was reduced from 75% to 20% in infected wt-HuH-7 cells. The difference in JNK activity translated into a differential AP-1 activation in the two cell lines. The initial AP-1 activity in untreated Trf1 cells was only 25% of that found in wt-HuH-7 cells. TNF treatment resulted in a 1.5 fold increase of AP-1 dependent reporter transcription in both cell lines thereby retaining the initial differential. DEN infection increased AP-1 activity in wt-HuH-7, while activity remained unchanged or slightly decreased in Trf1 cells. Consistent with a pro-apoptotic role for JNK, pretreatment with the JNK inhibitor SP600125 reduced TNF and DEN induced cell death in wt-HuH-7 by more than three fold. CONCLUSION: These results suggest a role for the JNK/c-Jun/AP-1 signal cascade in the regulation of a critical CK2alpha" dependent pro-apoptotic step in HuH-7 cells.

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