title: A functional interaction of E7 with B-Myb-MuvB complex promotes acute cooperative transcriptional activation of both S- and M-phase genes. (129 c).
abstract: High-risk human papillomaviruses are causative agents of cervical cancer. Viral protein E7 is required to establish and maintain the pro-oncogenic phenotype in infected cells, but the molecular mechanisms by which E7 promotes carcinogenesis are only partially understood. Our transcriptome analyses in primary human fibroblasts transduced with the viral protein revealed that E7 activates a group of mitotic genes via the activator B-Myb-MuvB complex. We show that E7 interacts with the B-Myb, FoxM1 and LIN9 components of this activator complex, leading to cooperative transcriptional activation of mitotic genes in primary cells and E7 recruitment to the corresponding promoters. E7 interaction with LIN9 and FoxM1 depended on the LXCXE motif, which is also required for pocket protein interaction and degradation. Using E7 mutants for the degradation of pocket proteins but intact for the LXCXE motif, we demonstrate that E7 functional interaction with the B-Myb-MuvB complex and pocket protein degradation are two discrete functions of the viral protein that cooperate to promote acute transcriptional activation of mitotic genes. Transcriptional level of E7 in patient's cervical lesions at different stages of progression was shown to correlate with those of B-Myb and FoxM1 as well as other mitotic gene transcripts, thereby linking E7 with cellular proliferation and progression in cervical cancer in vivo. E7 thus can directly activate the transcriptional levels of cell cycle genes independently of pocket protein stability.
authors.affiliation: 1] Institute of Medical Biology, A*STAR, Immunos #06-05, 8A Biomedical Grove, Singapore [2] Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
authors.forename: C L
authors.initials: CL
authors.lastname: Pang
authors.affiliation: Institute of Medical Biology, A*STAR, Immunos #06-05, 8A Biomedical Grove, Singapore.
authors.forename: S Y
authors.initials: SY
authors.lastname: Toh
authors.affiliation: Institute of Medical Biology, A*STAR, Immunos #06-05, 8A Biomedical Grove, Singapore.
authors.forename: P
authors.initials: P
authors.lastname: He
authors.affiliation: Institute of Medical Biology, A*STAR, Immunos #06-05, 8A Biomedical Grove, Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Teissier
authors.affiliation: Lyssavirus dynamics and host adaptation, Pasteur Institute, 25 rue Dr Roux, Paris, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Ben Khalifa
authors.affiliation: Institute of Medical Biology, A*STAR, Immunos #06-05, 8A Biomedical Grove, Singapore.
authors.forename: Y
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Institute of Medical Biology, A*STAR, Immunos #06-05, 8A Biomedical Grove, Singapore.
authors.forename: F
authors.initials: F
authors.lastname: Thierry
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D052162:Human papillomavirus 16 / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008938:Mitosis; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*
chemical_list: D018797:Cell Cycle Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C501563:LIN9 protein, human; C064352:MYBL2 protein, human; D009687:Nuclear Proteins; D050725:Papillomavirus E7 Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins