A functional interaction of E7 with B-Myb-MuvB complex promotes acute cooperative transcriptional activation of both S- and M-phase genes. (129 c)
Authors
CL Pang, SY Toh, P He, S Teissier, Y Ben Khalifa, Y Xue and F Thierry
Institution
A Star
Country
Singapore
Year
2013
Journal
Oncogene
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.
Oncogene advance online publication, 21 October 2013; doi:10.1038/onc.2013.426
Keywords: B-Myb-MuvB complex; HPV E7; B-Myb; FoxM1; mitosis; cervical carcinoma