Disease relevance of E6

• Human papillomavirus type 16 (HPV-16) is a DNA tumor virus that is associated with human anogenital cancers and encodes two transforming proteins, E6 and E7 [1].
• A recombinant vaccinia virus encoding human papillomavirus types 16 and 18, E6 and E7 proteins as immunotherapy for cervical cancer [2].
• The transcriptional promoter of the candidate E6-E7 transforming gene region of human papillomavirus (HPV)-16 (P97) was active in transiently transfected cervical carcinoma cells when linked to the HSV-1 tk or bacterial cat genes [3].
• To investigate the role of HPV-16 oncoproteins in the development of cancer metastasis, the E6 and E7 genes from HPV-16 were inserted into retrovirus and introduced into nonmetastatic mouse cell lines [4].
• The low-risk HPV-6 E6 and E7 proteins did not induce such abnormalities [5].

High impact information on E6

• E6 is an oncoprotein which cooperates with E7 to immortalize primary human keratinocytes [6].
• In lenses from neonatal E6 x E7 double transgenic mice, the level of apoptosis was reduced compared with that seen in lenses from neonatal E7 mice [7].
• Altered cell cycle regulation in the lens of HPV-16 E6 or E7 transgenic mice: implications for tumor suppressor gene function in development [7].
• To study the potential role of p53 and Rb in murine lens morphogenesis, we generated transgenic mice in which the expression of E6 or E7 was directed to the developing lens [7].
• Experiments were planned to evaluate the role of cell-mediated immunity (e.g., lymphocyte proliferation) against HPV in the natural history of HPV-associated neoplasia and to identify antigenic sequences of the HPV16 proteins E6 and E7 against which an immune response may confer protection [8].

Chemical compound and disease context of E6

• These data indicate that HPV-16 E6 and E7 oncogenes are mutagenic in human oral keratinocytes and enhance the mutagenic effect of MNNG [9].
• These data suggest that the acute loss of p53 function in HMECs by expression of HPV-16 E6 results in marked sensitivity to tamoxifen-mediated apoptosis but that resistance to apoptosis rapidly develops within 10 passages in vitro [10].

Biological context of E6

• These results provide a possible link between E6-induced oncogenesis and the insulin-stimulated cell proliferation signaling pathway [11].
• Here, we report that the transcription of the inhibitor of apoptosis gene, cellular inhibitor of apoptosis protein 2, (c-IAP2), is significantly upregulated in HPV16 E6/E7-immortalized human oral keratinocytes (HOK16E6E7) [12].
• Thus, upregulation of c-IAP2 by E6 and E7 may confer resistance to apoptosis that is necessary for sustained growth of some HPV16- and HPV18-positive cancer cells [12].
• Moreover, depletion of endogenous c-IAP2 using RNA interference in HOK16E6E7 induced apoptosis, indicating that c-IAP2 is necessary for HPV16 E6/E7-induced resistance to apoptosis and cell survival [12].
• These data indicate that the E6 and E5 ORFs are evolving under positive Darwinian selection and have done so in a relatively short time period [13].

Anatomical context of E6

• HPV16 E6 expression sensitized human (H4 and C33A) and murine (MCA-102) cell lines to lysis by macrophages but not by NK cells [14].
• We show that E6 proteins from benign human papillomavirus type 1 (HPV1) and oncogenic HPV16 have the ability to alter the regulation of the G(1)/S transition of the cell cycle in primary human fibroblasts [15].
• In summary, Ad5 E1A and HPV16 E6 sensitized cells to lysis by macrophages [14].
• Similar to what we found in histopathological specimens, HPV-16 E6 and E7 oncoproteins cooperate to induce abnormal centrosome numbers, aberrant mitotic spindle pole formation, and genomic instability [5].
• Leukoregulin (LR) and recombinant gamma-interferon (r-IFN-gamma), lymphokines secreted by immune cells present in regressing HPV infections, inhibited transcription of E6/E7 RNAs in several human cervical epithelial cell lines immortalized by recombinant HPV-16, -18, and -33 DNAs. r-IFN alpha was not effective [16].

Associations of E6 with chemical compounds

• A DILG motif and an ELVG motif located in the carboxyl-terminal of Tuberin are required for E6 binding [11].
• Furthermore, intratumor injection of DNA-liposome complex containing either E6 or E7 antisense plasmid resulted in significant growth inhibition of C3 tumors but not BL6 tumors, grown in a syngeneic mouse model [17].
• We previously reported that human keratinocytes (HKc) immortalized by transfection with human papillomavirus type 16 DNA (HKc/HPV16) are more sensitive than normal HKc to growth inhibition by retinoic acid (RA), and that RA treatment of HKc/HPV16 inhibits HPV16 E6/E7 mRNA expression (L. Pirisi et al., Cancer Res., 52: 187-193, 1992) [18].
• Phosphorothioate oligonucleotides (ODNs) AE6 and AE7 complementary to regions flanking the start codons of HPV16 E6 and E7 genes, respectively, were synthesized [19].
• Analysis of a series of c-fos promoter mutants indicates that the activation by both E6 and E7 is dependent on the cyclic AMP response element [20].

Regulatory relationships of E6

• Thus our results suggest a model whereby HPV-16 E7 induces centrosome-related mitotic disturbances that are potentiated by HPV-16 E6 [5].
• Previous studies have shown that loss of the viral E2 protein during malignant progression is an important feature of HPV-induced malignancy due to the resulting uncontrolled expression of the viral oncoproteins E6 and E7 [21].

Other interactions of E6

• Overexpression of E6/E7 from the high-risk HPV16 or 18, but not from the low-risk HPV6, activated c-IAP2 promoter [12].
• Further, the multiplex PCR for HPV16 E2 and E6 genes was performed for detection of integration [22].
• METHODS: The fragments of L1 and E6 genes were amplified by PCR or nested PCR and then directly sequenced [22].
• No particular patterns of variation in the URR, E6 or E2/E4 genes predicted physical state [23].

Analytical, diagnostic and therapeutic context of E6

• Our results demonstrate that both E6 and E7 abrogate the inhibition of DNA synthesis in the epidermis after treatment with ionizing radiation [24].
• These findings demonstrate that the E6 and E7 genes from a papillomavirus etiologically associated with human cervical cancer can contribute to the development of epidermal cancers in an animal model [25].
• In addition, the existence and expression of HPV 16 E6/E7 genes were detected in the lesions induced by ZE67 but not in the lesions of the control mice by analysis by polymerase chain reaction and mRNA in situ hybridization [26].
• In addition, protein levels of E6 and E7, as measured by immunofluorescence, are also decreased in a dose-dependent manner following RA treatment of HKc/HPV16 [18].
• This promising result indicates that E6/E7 antisense sequences expressed in the context of the U6 gene might be useful for gene therapy of cervical carcinoma [17].

References