A promoter within the E6 ORF of human papillomavirus type 16 contributes to the expression of the E7 oncoprotein from a monocistronic mRNA

Abstract

Human papillomavirus type 16 (HPV-16) has the capacity to transform human primary keratinocytes. Maintenance of the transformed phenotype requires constitutive expression of the oncoproteins E6 and E7. The low-risk HPV types express E7 from monocistronic mRNA, but for the high-risk types, no mRNA that encodes E7 as the first open reading frame (ORF) has been identified. We recently identified a transcription initiation site within the E6 ORF of HPV-16 at nt 542. In the present study we have characterized the P542 promoter, which putatively controls monocistronic expression of E7. The monocistronic mRNA is not very abundant, but we have shown that an E7-luciferase fusion protein can be expressed in SiHa cells from a monocistronic HPV-16 transcript initiated at nt 542. The monocistronic mRNA expresses E7-luciferase more efficiently than the most abundant in vivo-like mRNA E6*IE7, initiated by P97 and spliced from nt 226 to 409. Furthermore, the translation initiation of E7 is most abundant from the monocistronic mRNA. We have also shown that the P542 promoter is downregulated by the transcription factor activator protein 4 (AP-4) and the differentiation-dependent factor hSkn-1a, both binding downstream of the transcription initiation site. In conclusion, we have found that P542 is a relatively weak promoter compared with P97 and may be downregulated in differentiated epithelial cells.

AP4 activates cell migration and EMT mediated by p53 in MDA-MB-231 breast carcinoma cells

“…It was first found as an enhancer-binding factor of the SV40 (simian virus 40) late transcription in vitro by Mermod and colleagues [5]. In many studies, AP4 was found to participate in cellular differentiation, cell proliferation [6][7][8][9][10], cell cycle regulation, and apoptosis [11][12][13][14][15][16]. More recent findings show that AP4 is also involved in pathological conditions, for example, AP4 is highly expressed in colon carcinoma, breast cancer, and prostate cancer [15,17,18] and that AP4 suppresses MCF-7 cell proliferation via enhancing the levels of SHP1 and JNK activation [19].…”

Human papillomavirus gene expression is controlled by host cell splicing factors

“…Several other promoters which might play an important role in the viral life cycle have been identified [9][10][11][12][13]. Transcription of HPV late genes is only activated as HPVpositive cells start to differentiate [14,15].…”

Genome-Wide Prediction of Human Papilloma Virus Specific T-Cell Epitopes Using a Combination of Matrix Based Computational Tools

“…In India, it has been reported that 130,000 cases and 70-75,000 death occurred annually, suggesting that the cervical cancer is one of the major cancers in India [5]. Based on the carcinogenicity, HPV can be divided into two groups: high-risk types such as HPV 16 and 18 and low-risk types such as HPV type 6 and 11 [6]. More than 70% of cervical cancer is caused by both HPV type 16 and 18.…”