Effects of human papillomavirus type 16 oncoproteins on survivin gene expression

Abstract

Survivin has recently been identified as a novel member of the inhibitor of apoptosis (IAP) gene family. The product of this gene not only suppresses apoptosis but also controls cell division. Survivin is undetectable in most terminally differentiated normal tissues but is expressed in embryonic and fetal organs and is present in most malignant tumours. Human papillomaviruses (HPV) are thought to play an important role in the development of cervical cancer. By interfering in the cell cycle, the viral oncoproteins (E6 and E7) can induce the immortalization of the host cell. The transcriptional effects of the HPV-16 E6 and E7 proteins on the survivin promoter in transiently transfected cell lines using luciferase tests were examined. HPV-16 E6, but not E7, was found to significantly transactivate the survivin promoter. Experiments performed in different cancer cell lines and with different E6 mutants indicated that the effect of E6 on the survivin promoter is largely dependent on p53 status. In accordance with this, the p53 tumour suppressor protein downregulated the expression of survivin. As E6 is able to interact with p53 and induces its ubiquitin-dependent degradation, it appears that the transactivation effect of E6 on survivin is mediated by the p53 degradation pathway. Transduction of HPV-16 E6 and E7 into human embryonic fibroblast cells showed that the HPV oncoproteins can upregulate endogenous survivin mRNA. Importantly, cell cycle synchronization experiments showed that the effect of HPV-16 E6 on survivin transcription is independent of the cell cycle.

Role of HPV E6 proteins in preventing UVB-induced release of pro-apoptotic factors from the mitochondria

“…Whether this release was dependent upon Bak remains to be evaluated. The E6 protein of the oncogenic cervical HPV 16 was reported to increase Survivin expression, and that this was dependent upon the ability of the E6 protein to promote p53 proteolysis [41], although no increase in Survivin expression was seen in HeLa cells that express HPV18 E6, an E6 type that is also capable of promoting p53 degradation, as compared to non-HPV-containing cells [39]. However, as the E6 protein of cutaneous HPVs cannot promote p53 degradation is seems unlikely that this mechanism contributes towards cell survival, although this awaits further investigation.…”

Nuclear survivin expression is associated with HPV-independent carcinogenesis and is an indicator of poor prognosis in oropharyngeal cancer

“…It is well established that high-risk HPV E6 proteins induce the proteosome-mediated degradation of p53 and that the expression of p53 results in downregulation of survivin promoter constructs. Therefore, it is suggested that the transactivation effect of HPV16 E6 on survivin appears to be mediated by the p53 degradation pathway (Mirza et al, 2002;Borbely et al, 2006).…”

Scoring System and Management Algorithm Assessing the Role of Survivin Expression in Predicting Progressivity of HPV Infections in Precancerous Cervical Lesions

“…P53 supresses the expression of survivin, thus in conditions with loss of p53 function, such as cancer, expression of survivin is enhanced. HPV E6 induces the activity of survivin promoter region and increases endogenous survivin mRNA in human embryonic fibroblasts (Borbely, 2006;Mita, 2008) We propose a combined scoring system consisting of survivin expression by ICC and factors proved significant from multivariate analysis (Table 5). A biopsy will first be performed on the subject, classified to CIN 1, CIN 2, or CIN 3.…”