Merkel cell polyomavirus small T antigen induces genome instability by E3 ubiquitin ligase targeting.

This corrects the article DOI: 10.1038/onc.2017.277.

Merkel cell polyomavirus small T antigen induces genome instability by E3 ubiquitin ligase targeting.

The formation of a bipolar mitotic spindle is an essential process for the equal segregation of duplicated DNA into two daughter cells during mitosis. As a result of deregulated cellular signaling pathways, cancer cells often suffer a loss of genome integrity that might etiologically contribute to carcinogenesis. Merkel cell polyomavirus (MCV) small T (sT) oncoprotein induces centrosome overduplication, aneuploidy, chromosome breakage and the formation of micronuclei by targeting cellular ligases through a sT domain that also inhibits MCV large T oncoprotein turnover. These results provide important insight as to how centrosome number and chromosomal stability can be affected by the E3 ligase targeting capacity of viral oncoproteins such as MCV sT, which may contribute to Merkel cell carcinogenesis.

Dual effects of hepatitis C virus Core protein on the transcription of cyclin-dependent kinase inhibitor p21 gene.

Transcription of p21 was activated in hepatitis C virus (HCV) Core-expressing HepG2 cells where its upstream p53 was stabilized. However, this effect was not absolutely required for the activation of p21 by Core, as demonstrated in Hep3B cells. In addition, an opposite effect on the transcription of p21 was observed in NIH3T3 and primary hepatocytes, where p53 was not decreased by Core. To explain the p53-independent regulation of p21 by Core, we identified a Core-responsive element between positions -74 and -83 of the p21 promoter, exactly overlapped with a tumour growth factor beta (TGF-beta)/butyrate responsive element. Furthermore, we demonstrated that Core could activate the p21 through the element by stimulating a butyrate pathway, whereas this was inhibited through a TGF-beta pathway. The opposing effects of Core protein on the transcription of p21 might be important in understanding the progression of hepatic disease in HCV-positive patients.

Transcriptional repression of p21(waf1) promoter by hepatitis B virus X protein via a p53-independent pathway.

The X-gene product of hepatitis B virus (HBx) has been implicated in hepatitis B virus (HBV)-mediated hepatocellular carcinoma through its ability to induce liver cancer in some transgenic mice and to transactivate a variety of viral and cellular promoters. In this study, we demonstrated that the level of p21(waf1) RNA was decreased in the HBx-expressing cells and this effect was due to the transcriptional repression of the p21(waf1) gene by HBx via a p53-independent pathway. As the Sp1 binding sites of the p21(waf1) promoter were sufficient to confer HBx responsiveness to a previously non-responsive promoter, we suggested that HBx represses the transcription of p21(waf1) by downregulating the activity of Sp1. Because the tumor repressor p21(waf1) protein is a universal inhibitor of cyclin-CDK complexes and DNA replication that induces cell cycle arrest at the G1-S checkpoint, the repression of p21(waf1) by HBx might play an important role in a HBV-mediated pathogenesis.

Transcriptional regulation of herpes simplex virus type 1 ICP0 promoter by virion protein 16.

HSV regulatory proteins ICP0 and VP16 independently regulate transcription of the ICP0 gene during virus infection. In this study, we tried to determine the possible regulatory mechanism of ICP0 expression during virus infection. Among eight putative VP16 binding sites present in the ICP0 regulatory sequence, the most upstream one alone was sufficiently responsive to VP16-mediated activation. When the G/C-rich sequence present in front of the last TAATGARAT sequence of the ICP0 promoter was either deleted or point mutated, the activational effect of VP16 on the promoter was completely abolished. Furthermore, according to the gel mobility shift assay using a labeled double-stranded oligonucleotide derived from the G/C-rich sequence in the ICP0 promoter, specific protein binding to the probe was clearly demonstrated and was approximately fivefold upregulated by HSV-1 infection. Therefore, the G/C-rich sequence might play a critical role in VP16-mediated activation of the ICP0 promoter and the effect may be a result of the enhanced binding of a protein to the G/C-rich sequence during virus infection.

Activation of the thymidine kinase promoter by herpes simplex virus type 1 immediate early proteins.

The herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) gene promoter contains binding sites for the cellular transcription factors such as Spl, CTF, and TFIID, each of which affects basal level expression of the TK gene. The transcription of the TK gene was induced by viral immediate early proteins, ICP0 and ICP4 in an additive manner, but was repressed by ICP22 and ICP27. To gain further insights into the role of ICP0 and ICP4 for expression of the TK gene during virus infection, several mutants with deletions or point mutations in each of the transcriptional regulatory elements were generated starting at -109 and progressing toward +1. According to the CAT assay involving these mutants, the cellular transcription factor (CTF) binding site was necessary for efficient expression in the presence of transfected ICP0 and ICP4 or during virus infection, whereas the Sp1 binding site had a minor effect on ICP0-mediated TK expression. These results indicate that the immediate early proteins of HSV-1 regulate expression of the TK gene during virus infection by modulating activities of cellular transcription factors such as CTF.