Transformation by and Oncogenicity of Human Adenoviruses

Graham, Frank L.

doi:10.1007/978-1-4684-7935-5_9

Cited by 81 publications

(81 citation statements)

References 312 publications

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“…Then, the p53 and E4orf6 proteins were visualized with anti-p53 polyclonal antibody CM-1 and RSA3, respectively followed by enhanced chemiluminescence. expression of the E1A and E1B oncogenes (Graham, 1984). While E1A-immortalized BRK cells often resemble the primary parental cells (Houweling et al, 1980;Shiroki et al, 1981;Bernards et al, 1986) the apparent morphological changes associated with complete transformation by E1A and E1B are induced by a combinatorial e ect of both E1B proteins (White and Cipriani, 1990).…”

Section: Generation and Protein Analysis Of Transformed Brk Cellsmentioning

confidence: 99%

“…Full manifestation of the transformed phenotype requires expression of two E1B gene products, E1B-19 kDa and E1B-55 kDa, that are individually capable of cooperating with E1A to transform cells via independent but additive pathways (Barker and Berk, 1987;White and Cipriani, 1990;McLorie et al, 1991). Upon complete transformation, cells expressing E1A and E1B proteins grow rapidly and to high densities, display anchorage-independent growth, and are often tumorigenic (see review, Graham, 1984).…”

Section: Introductionmentioning

confidence: 99%

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The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53

et al. 1999

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The adenovirus type 5 (Ad5) E4orf6 protein promotes focus formation of primary baby rat kidney (BRK) cells in cooperation with Ad5 E1 proteins. This activity is most likely related to the ability of the E4orf6 protein to bind to p53 and modulate its tumor suppressor functions. In this study we report that transformed BRK cells that stably express E4orf6 in addition to E1A and E1B (ABS cells) displayed multiple additional properties commonly associated with a high grade of oncogenic transformation compared to cells expressing only E1A and E1B (AB cells). These properties included morphological alterations, markedly enhanced growth rates and growth to much higher saturation densities. Following injection into nude mice ABS-derived tumors exhibited accelerated growth and, based on histopathological criteria, proofed to be much more malignant compared to tumors generated by AB cells. Interestingly, these highly transformed properties of ABS cells correlated with a dramatic reduction of p53 steady-state levels which inversely correlated with E4orf6 expression. From these results we conclude that expression of the Ad5 E4orf6 protein (i) confers additional transformed in vitro properties to primary rat cells expressing the Ad5 E1 proteins, and (ii) increases the tumorigenic and malignant potential of these cells in vivo. Our data suggest that the Ad5 E4orf6 protein enhances the intrinsic ability of E1-transformed rat cells to grow in a neoplastic state by completely inactivating p53 tumor suppressor function in combination with the E1A and E1B proteins.

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Section: Generation and Protein Analysis Of Transformed Brk Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53

et al. 1999

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“…Interestingly, the majority of these cells lack E1A-and E4-speci®c sequences indicating that transformation occurred through a`hit-and-run' mechanism (Nevels et al, 2001). These observations together with the ®ndings for E4 ORF1 contradict the conventional concept of Ad-induced transformation (reviewed in Graham, 1984) and support the idea that the oncogenic potential of human Ads is not exclusively determined by the E1A and E1B gene products. In this article we will summarize the current information that relates to E4 gene function in viral oncogenesis.…”

Section: Introductionmentioning

confidence: 78%

“…In humans they are associated with a variety of clinical syndromes (reviewed in Horwitz, 1996), with over 50 distinct adenovirus (Ad) serotypes having been identi®ed and allocated to six subgroups (A through F). Although these viruses are not associated with human cancers, a subset of them, including all subgroup A and B viruses have the capacity to promote tumors (mostly undi erentiated sarcomas) in both male and female rodents at the site of injection (reviewed in Graham, 1984). Their transforming and oncogenic properties have been traditionally ascribed to functions in early region 1 (E1) which encodes the classical Ad E1A and E1B oncoproteins (reviewed in Nevins and Vogt, 1996).…”

Section: Introductionmentioning

confidence: 99%

Adenovirus early E4 genes in viral oncogenesis

Täuber

Dobner

2001

Oncogene

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Previous investigations into potential transforming activities of adenovirus (Ad) early genes were largely overshadowed by the more obvious roles of E1A and E1B products. One exception was an Ad9 E4 protein (ORF1) shown to enhance transformation of cultured cells and promote mammary tumors in female rats. Recently, signi®cant advances in understanding Ad E4 gene products at the molecular level have revealed that these proteins possess an unexpectedly diverse collection of functions, which not only orchestrate many viral processes, but overlap with oncogenic transformation of primary mammalian cells. Operating through a complex network of protein interactions with key viral and cellular regulatory components, Ad E4 products are apparently involved in transcription, apoptosis, cell cycle control, DNA repair, cell signaling, posttranslational modi®cations and the integrity of nuclear multiprotein complexes known as PML oncogenic domains (PODs). Some of these functions directly relate to known transforming and oncogenic processes, or implicate mechanisms such as modulating the function and subcellular localization of cellular PDZ domain-containing proteins, POD reorganization, targeted proteolytic degradation, inhibition of DNA double-strand break repair and`hit-and-run' mutagenesis. Here, we summarize the recent data and discuss how E4 gene product interactions may contribute to viral oncogenesis. Oncogene (2001) 20, 7847 ± 7854.

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“…Such transformed cells produced tumors only when they came from strains of virus that were directly oncogenic. 154 The use of live Ads as oral vaccines for ϳ30 years in millions of military recruits without any significant attributable complications would seem to be affirmative proof of the safety of human Ads as recombinant vaccine vectors.…”

Section: Applications In Vaccine Developmentmentioning

confidence: 99%

Development and application of adenoviral vectors for gene therapy of cancer

Zhang¹

1999

Cancer Gene Ther

165

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For successful gene vaccination and therapy of cancer, it is essential to develop gene delivery vectors that can meet clinical and social requirements. The need for improved vectors was clearly manifested during the peak of the first wave of gene therapy. Adenoviral (Ad) vectors have recently drawn the attention of many of those involved in the field of gene therapy for cancer because of their practical advantages and application potential. Many experiments, innovations, preclinical studies, and clinical trials have generated an overwhelming amount of data and literature concerning this vector system. It is hoped that the comprehensive review presented here, which includes the principles, potential, capacity, and limitations of the current Ad systems, will help to further the rational development of the system. The literature in this article is organized in an attempt to emphasize Ad vector development in the aspects of technical approaches, practical hurdles and strategies to overcome them, significant experimental results, recent advances, future directions, etc. The technical range of this review covers details that are intended to serve as a reference for advanced technical readers and provide a foundation for initiates in the field of Ad vector gene therapy. The material presented here is also intended for nontechnical persons who want to have an overview of the significance and potential of the technology.

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Transformation by and Oncogenicity of Human Adenoviruses

Cited by 81 publications

References 312 publications

The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53

The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53

Adenovirus early E4 genes in viral oncogenesis

Development and application of adenoviral vectors for gene therapy of cancer

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