Vaccinia virus-mediated cell cycle alteration involves inactivation of tumour suppressors associated with Brf1 and TBP.
The vaccinia virus (VV) replicates robustly and alters the progression of the cell cycle via an unknown mechanism. Herein, we provide evidence for the existence of a unique VV infection-induced cell cycle control mechanism. The regulation is correlated with the inactivation of p53 and Rb, which are associated with the RNA polymerase III transcription factor B (TFIIIB) subunits, TBP and Brf1 respectively. VV infection induced the expression of Mdm2 and its translocation into the nucleus, thereby resulting in a disruption of p53. VV also stimulated the expression of TFIIIB and TFIIIC, and consequently induced tRNA synthesis. On the other hand, the total level of Rb was not significantly influenced, but the level of hypo-phosphorylated Rb was enhanced, partially due to the VV-induced downregulation of cyclin-dependent kinases 4 and 6. However, the hypo-phosphorylated Rb appeared to be largely sequestered into a complex with Brf1, which resulted in the blockage of Rb function to repress E2F1 transactivation, thereby leading to a moderately higher proportion of cells in the S and G(2) phases. Conversely, the enforced expression of exogenous Rb restored the normally observed cell cycle patterns. Overall, these controls may contribute to the efficient replication of the virus in rapidly growing cells.
Yoo
Na-Kyung
NK
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Pyo
Chul-Woong
CW
Kim
Youngho
Y
Ahn
Byung-Yoon
BY
Choi
Sang-Yun
SY
D002453:Cell Cycle; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012320:RNA Polymerase III / Q000378:metabolism; D012343:RNA, Transfer / Q000096:biosynthesis; D035381:TATA-Binding Protein Associated Factors / Q000378:metabolism*; D035181:TATA-Box Binding Protein / Q000378:metabolism*; D035361:Transcription Factor TFIIIB / Q000096:biosynthesis; D019474:Transcription Factors, TFIII / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors*; D015854:Up-Regulation; D014616:Vaccinia virus / Q000502:physiology*; D000098832:Transcription Factor TFIIIC
C441028:BRF1 protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D035381:TATA-Binding Protein Associated Factors; D035181:TATA-Box Binding Protein; D035361:Transcription Factor TFIIIB; D019474:Transcription Factors, TFIII; D025521:Tumor Suppressor Proteins; D000098832:Transcription Factor TFIIIC; D012343:RNA, Transfer; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D012320:RNA Polymerase III