Individual adenovirus E1B proteins induce transformation independently but by additive pathways

McLorie, W; Cj, McGlade; Takayesu, D; Pe, Branton

doi:10.1099/0022-1317-72-6-1467

Cited by 43 publications

(36 citation statements)

References 31 publications

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“…E1A-immortalized cells are not completely transformed in that they grow slowly, and not to high densities, are anchorage dependent, and are not tumorigenic. 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%

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: 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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“…The E1B region encodes a 19 kD and a 55 kD protein, each with the capacity to cooperate with E1A in transforming cells (White and Cipriani, 1990;Barker and Berk, 1987;Bernards et al, 1986;McLorie et al, 1991). The 55 kD protein has been found to interact with p53 (Yew and Berk, 1992) whereas the 19 kD protein interacts with the death promoting Bax protein (Han et al, 1996) resulting in the inhibition of apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of p53-mediated transactivation and cell cycle arrest by E1A through its p300/CBP-interacting regionSelfcloseTable

1997

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“…Adenoviral proteins that protect infected cells against antiviral defenses include E3 gene products, such as the 19-kDa glycoprotein that sequesters major histocompatibility complex class I molecules in the endoplasmic reticulum and several small proteins that prevent induction of apoptosis in response to external signals (20). The two major E1B proteins, either of which can cooperate with E1A proteins to transform rodent cells (4,50), can also block apoptosis. The E1B 19-kDa protein was the first viral homologue of a cellular antiapoptotic protein to be identified.…”

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confidence: 99%

The Adenoviral E1B 55-Kilodalton Protein Controls Expression of Immune Response Genes but Not p53-Dependent Transcription

Miller

Rickards

Mashiba

et al. 2009

J Virol

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The human adenovirus type 5 (Ad5) E1B 55-kDa protein modulates several cellular processes, including activation of the tumor suppressor p53. Binding of the E1B protein to the activation domain of p53 inhibits p53-dependent transcription. This activity has been correlated with the transforming activity of the E1B protein, but its contribution to viral replication is not well understood. To address this issue, we used microarray hybridization methods to examine cellular gene expression in normal human fibroblasts (HFFs) infected by Ad5, the E1B 55-kDa-protein-null mutant Hr6, or a mutant carrying substitutions that impair repression of p53-dependent transcription. Comparison of the changes in cellular gene expression observed in these and our previous experiments (D. L. Miller et al., Genome Biol. 8:R58, 2007) by significance analysis of microarrays indicated excellent reproducibility. Furthermore, we again observed that Ad5 infection led to efficient reversal of the p53-dependent transcriptional program. As this same response was also induced in cells infected by the two mutants, we conclude that the E1B 55-kDa protein is not necessary to block activation of p53 in Ad5-infected cells. However, groups of cellular genes that were altered in expression specifically in the absence of the E1B protein were identified by consensus k-means clustering of the hybridization data. Statistical analysis of the enrichment of genes associated with specific functions in these clusters established that the E1B 55-kDa protein is necessary for repression of genes encoding proteins that mediate antiviral and immune defenses.The genomes of human subgroup C adenoviruses, such as adenovirus type 5 (Ad5), encode more than 20 proteins that are made prior to the onset of viral DNA synthesis in infected cells (reviewed in reference 1). The great majority of these immediate-early and early viral gene products interact with cellular proteins to optimize expression of viral genes or to block potentially deleterious host responses to infection. The 289R and 243R E1A proteins are prime examples of the former class. The larger E1A protein binds via a unique internal sequence to a specific subunit of the host cell mediator, a component of the RNA polymerase II transcriptional machinery, to stimulate transcription from viral early promoters by this enzyme in vitro and in infected cells (7,77,85). The 243R E1A protein interacts with the Rb protein and the related family members p107 and p130 to liberate transcriptional regulators of the E2F family, which are required for efficient transcription from the viral E2 early promoter (2, 13). This interaction is also crucial for the mitogenic and transforming activities of the E1A proteins. Adenoviral proteins that protect infected cells against antiviral defenses include E3 gene products, such as the 19-kDa glycoprotein that sequesters major histocompatibility complex class I molecules in the endoplasmic reticulum and several small proteins that prevent induction of apoptosis in response to external signa...

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Individual adenovirus E1B proteins induce transformation independently but by additive pathways

Cited by 43 publications

References 31 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

Inhibition of p53-mediated transactivation and cell cycle arrest by E1A through its p300/CBP-interacting regionSelfcloseTable

The Adenoviral E1B 55-Kilodalton Protein Controls Expression of Immune Response Genes but Not p53-Dependent Transcription

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