A functional interaction of E7 with B-Myb-MuvB complex promotes acute cooperative transcriptional activation of both S- and M-phase genes. (129 c)

• Published in: Oncogene Vol. 33; no. 31; pp. 4039 - 4049
• Main Authors: Pang, C L, Toh, S Y, He, P, Teissier, S, Ben Khalifa, Y, Xue, Y, Thierry, F
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-07-2014; Nature Publishing Group
• Subjects: 631/337/572; 631/67/1517/1371; 631/67/1858; 692/420/755; Apoptosis; Cancer; Carcinogenesis; Cell Biology; Cell Cycle Proteins - metabolism; Cell division; Cell Line, Tumor; Cells, Cultured; Cervical cancer; Female; Forkhead Box Protein M1; Forkhead Transcription Factors - metabolism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic research; Genetic transcription; Genetics; HEK293 Cells; HeLa Cells; Human Genetics; Human papillomavirus; Human papillomavirus 16 - metabolism; Humans; Internal Medicine; Keratinocytes - metabolism; Medicine; Medicine & Public Health; Mitosis; Molecular biology; Mutation; Nuclear Proteins - metabolism; Oncology; Oncology, Experimental; original-article; Papillomavirus E7 Proteins - genetics; Papillomavirus E7 Proteins - metabolism; Papillomaviruses; Properties; Proteins; S Phase; Trans-Activators - metabolism; Transcriptional Activation; Tumor Suppressor Proteins - metabolism; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology; Viral proteins; B-Myb-MuvB complex; B-Myb; mitosis; FoxM1; cervical carcinoma; HPV E7
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.426

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.