Requirement for the Adenovirus type 9 E4 Region in Production of Mammary Tumors

Javier, Ronald T.; Raska, K; Shenk, Thomas

doi:10.1126/science.1519063

Cited by 58 publications

(61 citation statements)

References 49 publications

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“…In animals, subgroup A and B adenoviruses produce undifferentiated sarcomas at the site of virus injection, and the viral E1 region, consisting of the E1A and E1B genes, is both necessary and sufficient for this tumorigenicity. The transforming potentials of the nuclear E1A and E1B oncoproteins derive, at least in part, from an ability to complex with and inactivate the cellular tumor suppressor proteins pRB and p53, respectively (2).…”

mentioning

confidence: 99%

“…Compared with the subgroup A and B adenoviruses, subgroup D adenovirus type 9 (Ad9) is unique in eliciting only estrogen-dependent mammary tumors in female rats (3) and requiring the viral E4 region ORF1 gene (9ORF1) for oncogenicity (4,5). The 9ORF1 gene codes for a 14-kDa cytoplasmic transforming protein (5,6), and three separate regions of this viral polypeptide are important for transforming potential in cells (7), including a C-terminal region that mediates direct binding to several unidentified cellular proteins (p220, p180, p160, p155, p140͞p130; R.S.W.…”

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confidence: 99%

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Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein

Lee

Weiss

Javier

1997

Proc. Natl. Acad. Sci. U.S.A.

373

342

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The 9ORF1 gene encodes an adenovirus E4 region oncoprotein that requires a C-terminal region for transforming activity. Screening a gt11 cDNA expression library with a 9ORF1 protein probe yielded a novel cellular PDZ domain-containing protein, 9BP-1, which binds to wildtype, but not a transformation-defective, C-terminal, mutant 9ORF1 protein. The fact that PDZ domains complex with specific sequences at the free C-terminal end of some proteins led to the recognition that the 9ORF1 C-terminal region contained such a consensus-binding motif. This discovery prompted investigations into whether the 9ORF1 protein associates with additional cellular proteins having PDZ domains. It was found that the 9ORF1 protein interacts directly, in vitro and in vivo, with the PDZ domain-containing protein hDlg͞SAP97 (DLG), which is a mammalian homolog of the Drosophila discs large tumor suppressor protein and which also binds the adenomatous polyposis coli tumor suppressor protein. Of interest, in forming complexes, the 9ORF1 protein preferentially associated with the second PDZ domain of DLG, similar to adenomatous polyposis coli protein. Human T cell leukemia virus type 1 Tax and most oncogenic human papillomavirus E6 oncoproteins also possessed PDZ domainbinding motifs at their C termini and, significantly, human T cell leukemia virus type 1 Tax and human papillomavirus 18 E6 proteins bound DLG in vitro. Considering the requirement of the 9ORF1 C-terminal region in transformation, these findings suggest that interactions with the cellular factor DLG may contribute to the tumorigenic potentials of several different human virus oncoproteins.Human adenoviruses are organized into six subgroups, A through F, and in people cause primarily respiratory, gastrointestinal, and eye infections (1). After infection of rodents, however, subgroup A and B and some subgroup D adenoviruses are tumorigenic. In animals, subgroup A and B adenoviruses produce undifferentiated sarcomas at the site of virus injection, and the viral E1 region, consisting of the E1A and E1B genes, is both necessary and sufficient for this tumorigenicity. The transforming potentials of the nuclear E1A and E1B oncoproteins derive, at least in part, from an ability to complex with and inactivate the cellular tumor suppressor proteins pRB and p53, respectively (2).Compared with the subgroup A and B adenoviruses, subgroup D adenovirus type 9 (Ad9) is unique in eliciting only estrogen-dependent mammary tumors in female rats (3) and requiring the viral E4 region ORF1 gene (9ORF1) for oncogenicity (4, 5). The 9ORF1 gene codes for a 14-kDa cytoplasmic transforming protein (5, 6), and three separate regions of this viral polypeptide are important for transforming potential in cells (7), including a C-terminal region that mediates direct binding to several unidentified cellular proteins (p220, p180, p160, p155, p140͞p130; R.S.W. and R.T.J., unpublished work). To reveal the molecular mechanisms of the novel 9ORF1 oncoprotein, we sought to identify these 9ORF1-associated cel...

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mentioning

confidence: 99%

mentioning

confidence: 99%

Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein

Lee

Weiss

Javier

1997

Proc. Natl. Acad. Sci. U.S.A.

373

342

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“…Compared with the subgroup A and B Ads, subgroup D Ad9 is unique in eliciting only estrogen-dependent mammary tumors in female rats (Ankerst et al, 1974;Jonsson and Ankerst, 1977;Ankerst and Jonsson, 1989;Javier et al, 1991). By generating hybrids between Ad9 and the closely related non-tumorigenic Ad26 viruses the Ad9 oncogenic determinant was localized to a segment in the viral E4 region containing ORF1, ORF2 and ORF3 (Javier et al, 1991(Javier et al, , 1992Javier, 1994;Javier and Shenk, 1996).…”

Section: E4 Orf1mentioning

confidence: 99%

“…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). Although subgroup D Ads are non-oncogenic in hamsters (Trentin et al, 1962), subgroup D Ad9 elicits exclusively estrogen-dependent mammary tumors in female rats following subcutaneous or intraperitoneal injection (Javier et al, 1991;Javier and Shenk, 1996). Besides its unique oncogenicity, Ad9 is unusual among Ads in requiring viral functions located outside of the E1 region for tumor induction (Javier et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

“…Although subgroup D Ads are non-oncogenic in hamsters (Trentin et al, 1962), subgroup D Ad9 elicits exclusively estrogen-dependent mammary tumors in female rats following subcutaneous or intraperitoneal injection (Javier et al, 1991;Javier and Shenk, 1996). Besides its unique oncogenicity, Ad9 is unusual among Ads in requiring viral functions located outside of the E1 region for tumor induction (Javier et al, 1992). Several studies have now established that its tumorigenicity in animals is solely dependent on two viral early region 4 (E4) encoded functions, the product of open reading frame (ORF) 1 (Javier, 1994) and some unde®ned regulatory element overlapping ORF2 (Thomas et al, 1999(Thomas et al, , 2001.…”

Section: Introductionmentioning

confidence: 99%

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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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An Ovine Adenovirus Vector Lacks Transforming Ability in Cells That Are Transformed by AD5 E1A/B Sequences

Nevels

MacAvoy

et al. 2000

Virology

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Adenoviruses of the Mastadenovirus and Aviadenovirus genera are able to transform certain cell types and induce tumor formation in susceptible animals. For the mastadenoviruses the E1A/B sequences are largely responsible for these properties but E4 sequences may also be involved. The transforming sequences of the aviadenoviruses, which lack E1A/B and E4 homologues, have not yet been fully identified. The recent proposal for a third genus of adenoviruses, which apparently lack an E1A homologue and have weak E1B homology, prompted an examination of the transforming properties of ovine adenovirus OAV287 (OAV), the prototype member of the new group. When OAV and human adenovirus type 5 (Ad5) were used to infect primary rat embryo cells, transformed foci developed in Ad5- but not in OAV-infected cultures. Similarly, after plasmid transfection, baby rat kidney cells were transformed by Ad5 E1A/B but not by OAV sequences. When CSL503 cells, an ovine cell line that is permissive for OAV, were transfected with Ad5 E1A/B sequences, transformed foci again appeared. However, plasmids or fragments containing complete or partial OAV genome sequences did not detectably transform CSL503 cells under the same conditions. When Ad5 E1A/B sequences were incorporated into the complete OAV genome and transfected, transformed clones were again obtained, showing that the gene dosage and transfection conditions were not limiting for transformation. The provision of Ad5 E1A and OAV sequences in combination marginally increased the number of morphologically altered foci in baby rat kidney cells but failed to induce multilayered focus formation. The data suggest that OAV lacks transforming functions in the cell types examined. Additional information suggesting that OAV may have a fundamentally distinct strategy for replication compared with other Ads is discussed.

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Requirement for the Adenovirus type 9 E4 Region in Production of Mammary Tumors

Cited by 58 publications

References 49 publications

Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein

Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein

Adenovirus early E4 genes in viral oncogenesis

An Ovine Adenovirus Vector Lacks Transforming Ability in Cells That Are Transformed by AD5 E1A/B Sequences

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