NF-Y loss triggers p53 stabilization and apoptosis in HPV18-positive cells by affecting E6 transcription.
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.
Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, 41125 Modena, Italy.
Paolo
P
Benatti
Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, 41125 Modena, Italy.
Valentina
V
Basile
Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.
Diletta
D
Dolfini
Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, 41125 Modena, Italy.
Silvia
S
Belluti
Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, 41125 Modena, Italy.
Margherita
M
Tomei
Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, 41125 Modena, Italy.
Carol
C
Imbriano
D023081:CCAAT-Binding Factor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D006367:HeLa Cells; D052161:Human papillomavirus 18; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis* / Q000235:genetics; D030361:Papillomavirus Infections / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D023081:CCAAT-Binding Factor; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
CCAAT-box; HPV18; NF-Y; gene transcription; p53