NF-Y loss triggers p53 stabilization and apoptosis in HPV18-positive cells by affecting E6 transcription
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Paolo Benatti1,*, Valentina Basile1,*, Diletta Dolfini2, Silvia Belluti1, Margherita Tomei1, Carol Imbriano1
1Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, 41125 Modena, Italy
2Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy
*These authors have contributed equally to this work
Carol Imbriano, email: firstname.lastname@example.org
Keywords: NF-Y, CCAAT-box, HPV18, p53, gene transcription
Abbreviations: Human Papilloma Virus, HPV; Transcription Factor, TF; Long Control Region, LCR; Upstream Regulatory Region, URR
Received: November 10, 2015 Accepted: June 01, 2016 Published: June 13, 2016
The expression of the high risk HPV18 E6 and E7 oncogenic proteins induces the transformation of epithelial cells, through the disruption of p53 and Rb function. The binding of cellular transcription factors to cis-regulatory elements in the viral Upstream Regulatory Region (URR) stimulates E6/E7 transcription. Here, we demonstrate that the CCAAT-transcription factor NF-Y binds to a non-canonical motif within the URR and activates viral gene expression. In addition, NF-Y indirectly up-regulates HPV18 transcription through the transactivation of multiple cellular transcription factors. NF-YA depletion inhibits the expression of E6 and E7 genes and re-establishes functional p53. The activation of p53 target genes in turn leads to apoptotic cell death. Finally, we show that NF-YA loss sensitizes HPV18-positive cells toward the DNA damaging agent Doxorubicin, via p53-mediated transcriptional response.
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