A NEW ROLE OF HPV16 E7 ONCOPROTEIN, INDEPENDENT OF POCKET PROTEINS, IN TRANSCRIPTIONAL ACTIVATION OF MITOTIC GENES

Abstract

High-risk human papillomaviruses (HPVs) are etiological agents of cervical cancers. Previous studies demonstrated that the viral oncoprotein E7 can up-regulate transcription of cellular E2F target genes and promote S-phase entry by subverting the pRB/E2F pathway. B-Myb and FoxM1 are major transcription factors of mitotic genes as well as E2F target genes that were found to be upregulated by E7 in our previous microarray. Both siRNA-mediated depletion assay and overexpression studies by lentiviral transduction revealed that 16E7 and B-Myb or FoxM1 play pivotal roles and act in co-operative manner to activate mitotic gene expression. Using ChIP and CoIP approaches, we demonstrate for the first time that E7 could be recruited to promoter of mitotic genes through protein-protein interaction with B-Myb, FoxM1 and/or DREAM complex. Collectively, our findings propose a novel pRB-independent function of E7 in promoting oncogenic transformation, and shed light on the involvement of B-Myb/FoxM1/MuvB activator complex in cervical carcinogenesis.