The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1A

Phelps, William C.; Yee, Carole; Münger, Karl; Howley, Peter M.

doi:10.1016/0092-8674(88)90570-3

Cited by 629 publications

(478 citation statements)

References 47 publications

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“…Additionally, the E7 oncoprotein contains several identified MHC I CTL epitopes [26]. However, although DNA vaccination appears to be a safe means to deliver HPV antigens, DNA vaccination with oncogenes still harbors the risk of transformation for the cells that receive and express the oncogenes [27,28]. Thus E7 based vaccine strategies seek to simultaneously eliminate or reduce the transforming ability and enhance the immunogenic potential of the E7 oncoprotein.…”

Section: Discussionmentioning

confidence: 99%

The efficacy of a DNA vaccine containing inserted and replicated regions of the E7 gene for treatment of HPV-16 induced tumors

Brinkman

Kast

2007

Vaccine

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A majority of cervical cancers are associated with HPV-16. A DNA vaccine (E7IR) was designed for prophylactic and therapeutic treatment of HPV-16+ tumors containing two repeats of the E7 gene to inactivate transformation and duplicate available epitopes. Mice were vaccinated then tumor challenged, or challenged and then immunized and monitored for tumor volume and survival. Splenocytes were utilized for in vivo CTL assays. The E7IR vaccine demonstrated decreased tumor volume and enhanced survival in prophylactic and therapeutic experiments and improved CTL mediated lysis. The E7IR vaccine shows promise in prevention of tumor formation and elimination of established tumors. KeywordsHuman Papillomavirus (HPV); DNA Vaccine; Cervical Cancer 1.IntroductionCancer of the uterine cervix is the second most common cause of cancer-related deaths in women worldwide. Approximately 510,000 new cases and 288,000 deaths are reported annually [1]. The development of cervical cancer is associated with infection with high risk types of Human Papillomaviruses (HPV). HPV is detected in 99.7% of cervical carcinomas [2], with high risks types HPV-16 and 18 accounting for nearly 70% of cervical cancer cases [3]. In contrast to many other cancers, the fact that cervical cancer is highly associated with a viral infection creates a unique opportunity for therapeutic vaccination against HPV to either prevent cervical cancer once an individual is infected or after the virus has caused cervical cancer. Integration of the viral genome into the host cell genome, a necessary step in cellular transformation, leads to the loss of some genes necessary for a productive viral life cycle and to deregulated or overexpression of the E6 and E7 oncoproteins. Because E7 has been shown to be consistently expressed in HPV-16 positive tumors, it is a logical target in HPV-16 vaccination strategies. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Preclinical studies using DNA based vaccine approaches tend to focus on enhancing presentation of HPV antigens via the MHC class I or MHC class II pathways [5]. Several different approaches have been examined including the attachment of ubiquitin to DNA constructs [6,7], targeting of tumor antigens to centrosomal compartments to enhance MHC class I presentation [8], the attachment to constructs of calreticulin to target HPV antigens to the MHC I pathway [9], optimization of codon usage for enhanced expression and presentation of HPV oncogenes [6,10,11] , utilization of modified genes to decrease the transformation capacity [12][13][14] or enhancement of intercellular s...

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Section: Discussionmentioning

confidence: 99%

The efficacy of a DNA vaccine containing inserted and replicated regions of the E7 gene for treatment of HPV-16 induced tumors

Brinkman

Kast

2007

Vaccine

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“…While CR1 and CR2 share structural and functional homologies with the corresponding Adenovirus E1A and Polyomavirus large T antigen regions, the zinc-finger domain appears unique and does not have a homologous in the E1A or in the large T antigen molecules. In particular, HPV E7 CR2 region shares a small block of amino-acid sequence similarity with Adenovirus E1A and Polyomavirus large T antigens (Phelps et al, 1988;Vousden and Jat, 1989) (Figure 1). This sequence contains the LxCxE motif, the canonical binding site for pRb and the related pocket proteins p107 and pRb2/p130 which negatively regulate progression from G0 through G1 and into the S phase of cell cycle (Dyson et al, 1989a, b;Davies et al, 1993;Hu et al, 1995).…”

Section: Human Papillomavirus E7mentioning

confidence: 99%

Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins

Mileo²,

2006

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“…HPV16 E7 is structurally and functionally related to adenovirus E1A (Phelps et al, 1988). Both viral proteins induce stabilization and accumulation of the transcription factor p53 (Debbas and White, 1993;Demers et al, 1994;Hickman et al, 1994;Lowe and Ruley, 1993;Querido et al, 1997;Samuelson and Lowe, 1997;Slebos et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts

et al. 2000

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The HPV16 E7 oncoprotein neutralizes several cell cycle checkpoints, favouring the entry of quiescent cells into S phase. This activity is mediated in part by association of E7 with the pocket proteins and consequent activation of E2F transcription factors. In addition, HPV16 E7 protein is able to promote apoptosis. In this study we demonstrate that the ability to induce apoptosis is a common property of E7s belonging to both benign and malignant HPV types. The E7-induced apoptosis is mediated by inactivation of pRb, whilst neutralization of the other two pRB-related proteins, p107 and 130, is not su cient to trigger apoptosis. Moreover, we show that certain point mutations in the conserved region 1 (CR1) of HPV16 E7 abolish the induction of apoptosis without altering the ability to stimulate S phase. Thus, these two E7-mediated cellular events, apoptosis and S phase entry, can be separated in immortalized rodent ®broblasts. Our ®ndings demonstrate that the E7-mediated pRb destabilization is not required for its ability to drive quiescent cells into S phase and to induce apoptosis. Finally, expression of E7 proteins in NIH3T3, which lack a functional p19 ARF , does not lead to p53 accumulation, indicating that the E7 impacts upon additional cellular pathways to promote apoptosis.

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The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1A

Cited by 629 publications

References 47 publications

The efficacy of a DNA vaccine containing inserted and replicated regions of the E7 gene for treatment of HPV-16 induced tumors

The efficacy of a DNA vaccine containing inserted and replicated regions of the E7 gene for treatment of HPV-16 induced tumors

Retinoblastoma family proteins as key targets of the small DNA virus oncoproteins

Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts

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