Allison, Simon J., Jiang, Ming and Milner, Jo (2009) Oncogenic viral protein HPV E7 up-regulates the SIRT1 longevity protein in human cervical cancer cells. Aging, 1 (3). pp. 316-327.

Senescence is blocked in human cervical keratinocytes infected with high risk human papillomavirus (e. g. HPVtype16). Viral oncoproteins HPV E6 and HPV E7 access the cell cycle via cellular p53 and retinoblastoma proteinsrespectively. Previously we have shown that HPV E7, not HPV E6, is also responsible for cervical cancer cell survival (SiHacells; HPV type16). We now present evidence that SIRT1, an aging- related NAD- dependent deacetylase, mediates HPV E7survival function in SiHa cervical cancer cells. Moreover, HPV E7 up- regulates SIRT1 protein when expressed in primaryhuman keratinocytes. Conversely, SIRT1 levels decrease following RNAi- mediated silencing of HPV E7 in SiHa cells. SilencingHPV E6 has no effect on SIRT1 but, as expected, causes marked accumulation of p53 protein accompanied by p53- mediated up-regulation of p21. However, p53 acetylation (K382Ac) was barely detectable. Since p53 is a known SIRT1 substrate we-propose that elevated SIRT1 levels (induced by HPV E7) attenuate p53 pro-apoptotic capacity via its de-acetylation. Our-discovery that HPV E7 up- regulates SIRT1 links a clinically important oncogenic virus with the multi-functional SIRT1protein. This link may open the way for a more in-depth understanding of the process of HPV-induced malignant-transformation and also of the inter- relationships between aging and cancer.

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