Regulation of p14ARF expression by HPV-18 E6 variants

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A common causative agent for uterine cervical cancer is the human papillomavirus type 18 (HPV-18) which has three phylogenic variants: Asian-Amerindian, European, and African. Each variant shows significant molecular differences in the E6 gene. E6 oncoprotein is a negative regulator of tumor suppressor protein p53, hence, this oncoprotein indirectly regulates the expression of tumor-suppressor p14ARF. p14ARF and p16INK4A genes are overexpressed in—and have been proposed as markers for—HPV-related cervical cancer. In order to dissect the role of E6 on the regulation of p14ARF expression, separating it from that of other intervening factors, transfection of E6 variants to MCF-7 cells was performed, assessing cDNA transcript levels by RT-PCR, whereas p14ARF and p53 expression were evaluated by immunocytochemistry and Western blot. E6 transfected cells differentially expressed transcripts of two molecular forms: E6 and E6*. The ratio of these two forms varied with the transfected E6 variant. With the Asian-Amerindian variant, the ratio was E6 > E6*, whereas with the European and the African the ratio was E6* > E6. As expected with the E6* construct, E6* transcripts were solely observed. In addition, when E6 > E6* and p53 expression was low, p14ARF was high and when E6* > E6 and p53 expression was high, p14ARF was low. In conclusion, each E6 variant distinctively affects p53 levels and consequently p14ARF expression, finding that could be related with the differences in oncogenic effect of infection with the diverse high-risk HPV variants.

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