High levels of Daxx due to low cellular levels of HSP25 in murine cancer cells result in inefficient adenovirus replication

다국어 초록 (Multilingual Abstract)

When the adenoviral protein E1B55K binds death domain-associated protein (Daxx), the proteasome-dependentdegradation of Daxx is initiated, and adenoviral replication is effectively maintained. Here, we show that the cellularlevels of Daxx differ between human and mouse cancer cell lines. Specifically, we observed higher cellular Daxx levelsand the diminished replication of oncolytic adenovirus in mouse cancer cell lines, suggesting that cellular Daxx levelslimit the replication of oncolytic adenoviruses that lack E1B55K in murine cells. Indeed, the replication of oncolyticadenoviruses that lack E1B55K was significantly increased following infection with oncolytic adenovirus expressingDaxx-specific shRNA. Cellular Daxx levels were decreased in mouse cells expressing heat shock protein 25 (HSP25;homolog of human HSP27) following heat shock or stable transfection with HSP25-bearing plasmids. Furthermore,Daxx expression in murine cell lines was primarily regulated at the transcriptional level via HSP25-mediated inhibitionof the nuclear translocation of the signal transducer and activator of transcription 3 (stat3) protein, which typicallyupregulates Daxx transcription. Conversely, human HSP27 enhanced stat3 activity to increase Daxx transcription.
Interestingly, human Daxx, but not mouse Daxx, was degraded as normal by ubiquitin-dependent lysosomaldegradation; however, HSP27 downregulation induced the ubiquitin-independent proteasomal degradation of Daxx.

참고문헌 (Reference)

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