Tumorigenicity of adenovirus-transformed cells: Region E1A of adenovirus 12 confers resistance to natural killer cells

Sawada, Yoko; Föhring, Bernd; Shenk, Thomas; Raska, K

doi:10.1016/0042-6822(85)90143-6

Cited by 72 publications

(43 citation statements)

References 29 publications

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“…These data are similar to reports that E1A gene products sensitize human and murine cells to TNF-␣ and Fas-dependent killing (10 -12). However, E1A gene products do not always sensitize human or rodent cells to lysis by immune mediators or effector cells (8,(31)(32)(33). Furthermore, the molecular basis for the increased susceptibility of E1A-expressing cells to TNF-␣ and Fas-dependent killing is unknown.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus E1A Oncogene Expression in Tumor Cells Enhances Killing by TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Routes

Ryan²,

Clase³

et al. 2000

The Journal of Immunology

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Expression of the adenovirus serotype 5 (Ad5) E1A oncogene sensitizes cells to apoptosis by TNF-α and Fas-ligand. Because TNF-related apoptosis-inducing ligand (TRAIL) kills cells in a similar manner as TNF-α and Fas ligand, we asked whether E1A expression might sensitize cells to lysis by TRAIL. To test this hypothesis, we examined TRAIL-induced killing of human melanoma (A2058) or fibrosarcoma (H4) cells that expressed E1A following either infection with Ad5 or stable transfection with Ad5-E1A. E1A-transfected A2058 (A2058-E1A) or H4 (H4-E1A) cells were highly sensitive to TRAIL-induced killing, but Ad5-infected cells expressing equally high levels of E1A protein remained resistant to TRAIL. Infection of A2058-E1A cells with Ad5 reduced their sensitivity to TRAIL-dependent killing. Therefore, viral gene products expressed following infection with Ad5 inhibited the sensitivity to TRAIL-induced killing conferred by transfection with E1A. E1B and E3 gene products have been shown to inhibit TNF-α- and Fas-dependent killing. The effect of these gene products on TRAIL-dependent killing was examined by using Ad5-mutants that did not express either the E3 (H5dl327) or E1B-19K (H5dl250) coding regions. A2058 cells infected with H5dl327 were susceptible to TRAIL-dependent killing. Furthermore, TRAIL-dependent killing of A2058-E1A cells was not inhibited by infection with H5dl327. Infection with H5dl250 sensitized A2058 cells to TRAIL-induced killing, but considerably less than H5dl327-infection. In summary, expression of Ad5-E1A gene products sensitizes cells to TRAIL-dependent killing, whereas E3 gene products, and to a lesser extent E1B-19K, inhibit this effect.

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Section: Discussionmentioning

confidence: 99%

Adenovirus E1A Oncogene Expression in Tumor Cells Enhances Killing by TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Routes

Ryan²,

Clase³

et al. 2000

The Journal of Immunology

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show abstract

“…E1A-induced cytolyticsusceptibility correlates well with tumor-cell rejection by immunocompetent animals (12)(13)(14)(15)(16)(17). The mechanisms by which E1A converts cells to a cytolytic-susceptible, nontumorigenic phenotype are independent of expression of the p53 tumor-suppressor gene (18) but are otherwise unknown.…”

mentioning

confidence: 92%

Role of the E1A Rb-binding domain in repression of the NF-κB-dependent defense against tumor necrosis factor-α

Cook

Walker

Worthen

et al. 2002

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

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“…The sensitivity of E1A-and E7-expressing murine and human tumor cells to killing by NK cells and macrophages in vitro directly correlates with their tumorigenicity in vivo (9,13,36,41,(47)(48)(49)(50)53). Thus, several lines of evidence suggest that the ability of the innate immune response to reject E1A-expressing cells but not E7-expressing cells influences the tumorigenicity of these cells.…”

mentioning

confidence: 95%

Expression of an E1A/E7 Chimeric Protein Sensitizes Tumor Cells to Killing by Activated Macrophages but Not NK Cells

Miura

Morris

et al. 2004

J Virol

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Adenovirus (Ad) E1A and human papillomavirus (HPV) E7 express homologous conserved regions (CRs) that mediate their shared biological functions. Despite their similarities, the expression of E1A sensitizes tumor cells to killing by NK cells and macrophages but the expression of E7 does not, a factor that may contribute to the dissimilar oncogenicities of Ad and HPV. This study was undertaken to define molecular differences between E1A and E7 that are responsible for the ability of E1A and the inability of E7 to sensitize cells to killing by NK cells and macrophages. Genetic mapping studies using human fibrosarcoma cells (H4) that stably expressed mutant forms of E1A showed that only those forms of E1A that interacted with the transcriptional coadaptor protein p300 sensitized cells to killing by NK cells and macrophages. E7 lacks the N-terminal p300-binding region present in E1A. Therefore, a chimeric E1A/E7 gene was constructed that included the N terminus and the CR1 (p300-binding) domain of E1A fused to CR2 and the C-terminal sequences of E7. The E1A/E7 protein interacted with p300 and pRb and immortalized primary mouse embryo fibroblasts (MEF). The expression of E1A/E7 sensitized H4 and MEF cells to killing by activated macrophages but not to killing by NK cells. Therefore, N-terminal differences between E1A and E7 that map to the E1A-p300 binding region accounted for differences in their abilities to sensitize cells to killing by macrophages. However, regions in addition to the E1A-p300 binding region are required to sensitize cells to killing by NK cells.Adenoviruses (Ad) and human papillomaviruses (HPV) are common human pathogens that express functionally analogous oncoproteins. Two viral oncoproteins are consistently expressed upon cellular transformation in HPV-induced malignancies or Ad-transformed cells (HPV E7 and E6; Ad E1A and E1B). The E1A and E7 oncoproteins express homologous conserved regions (CRs), CR1 and CR2. These CRs interact with and inhibit cellular growth regulatory proteins (pRb, p107, p130, and cyclin A) (20,27,(37)(38)(39)(40)52). CR1 and CR2 of E1A and E7 are interchangeable for cellular immortalization (6). Through different molecular mechanisms, the Ad E1B-55K and HPV E6 oncoproteins inhibit the function of p53, thereby complementing E1A and E7 in inducing cellular transformation.Despite the functional similarities in their transforming oncoproteins, Ad do not appear to be oncogenic in humans. In contrast, HPV are responsible for Ͼ95% of cervical carcinomas (5, 25). The inability of Ad to be oncogenic in humans is notable because Ad are fully competent to transform human cells (24) and Ad-transformed human cells form tumors in immunodeficient mice (13). These observations suggest that factors in addition to cellular transformation by Ad or HPV determine the oncogenicity of these viruses.The difference in the abilities of E1A and E7 to elicit an antitumor immune response is one factor that likely contributes to the dissimilar oncogenicities of Ad and HPV. In immunocompetent mice, tu...

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Tumorigenicity of adenovirus-transformed cells: Region E1A of adenovirus 12 confers resistance to natural killer cells

Cited by 72 publications

References 29 publications

Adenovirus E1A Oncogene Expression in Tumor Cells Enhances Killing by TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Adenovirus E1A Oncogene Expression in Tumor Cells Enhances Killing by TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Role of the E1A Rb-binding domain in repression of the NF-κB-dependent defense against tumor necrosis factor-α

Expression of an E1A/E7 Chimeric Protein Sensitizes Tumor Cells to Killing by Activated Macrophages but Not NK Cells

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