The two early HPV genes, E6 and E7, play an essential role in cellular transformation and abnormal proliferation. The oncoprotein E6 suppresses the activation of p53-dependent pathways through proteasomal degradation of p53 and inhibition of its transactivating activity. The CCAAT-binding factor NF-Y regulates the transcription of various genes related to the cell cycle. A biochemical and genetic link has been described between p53 and NF-Y: i) a large overlap of targets exists between NF-Y and p53, particularly many genes transactivated by NF-Y are repressed following p53 activation; ii) both wt and mutp53 proteins interact with NF-Y; iii) loss of NF-Y, as well as unrestricted activity, triggers cycle defects and p53-dependent cell death. Specifically, the inactivation of NF-YA, the DNA binding subunit of the NF-Y complex, leads to a delay in S phase progression and to the activation of a DNA-damage response. Here we show a novel mechanism through which NF-Y and p53 are connected in HPV-positive cells. The knock-down of NF-YA in Hela cervical carcinoma cells leads to p53 re-expression and re-activation of p53-dependent apoptosis. The analysis of microarray profiles of NF-YA inactivated versus control cells points at “p53 pathway” and “apoptosis” as the most represented KEGG pathways up-regulated following NF-Y loss. Western blot, RT-PCR, transient transfection and ChIP data clearly suggest that NF-Y positively regulates E6 expression, driven by HPV-18 upstream regulatory region, which contains two NF-Y binding sites. Consequently, NF-Y down-regulation by shRNA delivery results in E6 transcriptional repression and in the activation of p53 and its target genes. Our results demonstrate that NF-Y inactivation might represent an interesting anti-tumor strategy to induce apoptosis in high-risk HPV-infected cancer cells, through the re-establishment of p53 expression.
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|Titolo:||NF-Y LOSS REACTIVATES p53 AND TRIGGERS p53-DEPENDENT APOPTOSIS IN HPV-POSITIVE HUMAN CERVICAL CARCINOMA CELLS|
|Autori:||Benatti, Paolo; Mantovani, Roberto; Imbriano, Carol|
|Data di pubblicazione:||2014|
|Data del convegno:||15-19/06/2014|
|Luogo del convegno:||Stockholm|
|Appare nelle tipologie:||Poster|
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