Early viral proteins in HeLa cells infected with adenovirus type 5 host range mutants

Ross, Susan R.; Levine, Arnold J.; Galos, Richard S.; Williams, Jim; Shenk, Thomas

doi:10.1016/0042-6822(80)90205-6

Cited by 71 publications

(59 citation statements)

References 43 publications

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“…This suggestion is supported by several lines of evidence: (i) the viral proteins with which p53 interacts in DNA tumor virus-transformed cells are also required for viral DNA replication (8,10,25,29,30), (ii) the stimuli which increase the levels of p53 in nontransformed cells also induce DNA synthesis (7,22), and (iii) cellular transformation or neoplasia can generally be viewed as involving an abrogation of normal regulation of DNA synthesis. At present it is not possible to distinguish whether elevated levels of p53 have a * Corresponding author.…”

mentioning

confidence: 58%

UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells.

Maltzman¹,

Czyzyk²

1984

Mol. Cell. Biol.

799

411

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Elevated levels of the p53 cellular tumor antigen have been previously observed in proliferating and transformed mammalian cells. We found that nontransformed mouse cells treated with either UV light or a UV-mimetic chemical carcinogen exhibited a rapid increase in the amount of p53. This stimulation can be explained, at least in part, on the basis of a post-translational stabilization of p53 which is independent of replicative DNA synthesis, consistent with p53 not being an adventitious product of proliferating cells. The results presented here are interpreted in light of the general hypothesis that p53 is involved in the preparation of mammalian cells for DNA synthesis.The p53 cellular tumor antigen is a cellular protein originally observed (14, 17) in murine cells transformed by the DNA tumor virus simian virus 40 (SV40). Subsequently, it has been demonstrated that the levels of this protein are substantially elevated in a variety of systems (for a review, see reference 11), including cells of different mammalian species which have been neoplastically transformed by DNA tumor viruses, isolated from naturally occurring tumors, or stimulated by either mitogens or serum factors to synthesize DNA. The correlation between expression of high levels of p53 and some transformation events or other treatments stimulating cellular growth is reasonably firm and consistent with the hypothesis that p53 functions in the regulation of the transition of mammalian cells to active proliferation. However, the molecular mechanism by which p53 may affect such a transition is at present unknown.The regulation of expression, as well as the possible function, of p53 in neoplastically transformed cells has been most extensively examined in mouse cells transformed by SV40. It has been established that the elevated levels of p53 observed in SV40-transformed mouse cells are a function of the tight interaction (14,17,21,24) of this protein with the SV40-encoded large tumor antigen (T-Ag); this interaction manifests itself in a dramatic increase in the half-lives of both proteins (24). Because of these facts and other demonstrations that the levels of p53 are increased in DNA tumor virus-transformed and proliferating cells, it has been suggested that pS3 functions in the regulation of cellular growth by interacting with viral transforming gene products (22) in virus-transformed cells and, in normal cells, by interacting with a cellular protein(s) (7,15).In general, it is speculated that the precise molecular function of p53 in affecting the transition of cells to active DNA synthesis has to do with the initiation of DNA replication. This suggestion is supported by several lines of evidence: (i) the viral proteins with which p53 interacts in DNA tumor virus-transformed cells are also required for viral DNA replication (8,10,25,29,30), (ii) the stimuli which increase the levels of p53 in nontransformed cells also induce DNA synthesis (7,22), and (iii) cellular transformation or neoplasia can generally be viewed as involving an abrogation of ...

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mentioning

confidence: 58%

UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells.

Maltzman¹,

Czyzyk²

1984

Mol. Cell. Biol.

799

411

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“…The E1B 55-kDa protein neither participates directly in viral DNA synthesis (10) nor facilitates production of viral replication proteins during the early phase of infection in transformed or normal human cells (4,35,44,49,73). The results described above therefore suggest that, when synthesized in timely fashion, this early protein protects against inhibition of viral DNA synthesis by a cellular defense mechanism, such as the double-stranded DNA break repair response.…”

Section: Acceleration Of Early Phase Progression In Hffs Restores Effmentioning

confidence: 77%

Timely Synthesis of the Adenovirus Type 5 E1B 55-Kilodalton Protein Is Required for Efficient Genome Replication in Normal Human Cells

Chahal

Flint

2012

J Virol

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Previous studies have indicated that the adenovirus type 5 E1B 55-kDa protein facilitates viral DNA synthesis in normal human foreskin fibroblasts (HFFs) but not in primary epithelial cells. To investigate this apparent difference further, viral DNA accumulation was examined in primary human fibroblasts and epithelial cells infected by the mutant AdEasyE1⌬2347, which carries the Hr6 frameshift mutation that prevents production of the E1B 55-kDa protein, in an E1-containing derivative of AdEasy. Impaired viral DNA synthesis was observed in normal HFFs but not in normal human bronchial epithelial cells infected by this mutant. However, acceleration of progression through the early phase, which is significantly slower in HFFs than in epithelial cells, eliminated the dependence of efficient viral DNA synthesis in HFFs on the E1B 55-kDa protein. These observations suggest that timely synthesis of the E1B 55-kDa protein protects normal cells against a host defense that inhibits adenoviral genome replication. One such defense is mediated by the Mre11-Rad50-Nbs1 complex. Nevertheless, examination of the localization of Mre11 and viral proteins by immunofluorescence suggested that this complex is inactivated similarly in AdEasyE1⌬2347 mutant-infected and AdEasyE1-infected HFFs.T he E1B gene of species C human adenoviruses, such as adenovirus type 5 (Ad5), encodes unrelated proteins of 19 and 55 kDa that contribute to optimizing the environment for efficient viral replication within infected cells. The 19-kDa protein blocks apoptosis in infected cells (24,65,86,99) and was the first viral homologue of cellular anti-apoptotic proteins to be identified (20,85,88). The E1B 55-kDa protein also counteracts cellular responses to infection that would be detrimental to efficient virus reproduction. One of the first properties to be ascribed to the E1B 55-kDa protein was interaction with the cellular tumor suppressor p53 (76). In rodent cells transformed by E1A and E1B gene products, this interaction can sequester p53 in juxtanuclear cytoplasmic structures (13,42,107). Binding of the E1B 55-kDa protein to the N-terminal activation domain of p53 has also been reported to inhibit p53-dependent transcription both in in vitro reactions and in transient expression systems (54,105,106). Insertions or substitutions in the E1B protein that impaired E1B-dependent transcriptional repression were observed to reduce the ability of the E1B protein to cooperate with E1A gene products in transformation of rodent cells (55,89,90,106). Inhibition of p53-dependent transcription and transforming activity has also been reported to be reduced by a substitution that prevents sumoylation of the E1B 55-kDa protein at Lys104 (28), whereas substitutions that block shuttling of this protein between the nucleus and cytoplasm (25, 47) stimulate both activities (27). These observations indicate that inhibition of the transcriptional function of p53 and, presumably, of induction of apoptosis by this cellular protein are important for the transforming activity o...

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“…The potential involvement of E1B in the regulation of early gene expression has also been explored (Berk & Sharp, 1978;Ross et al, 1980b), but the results have not revealed as clear a role for E 1B products as has been found for E 1A and E2A. E 1B encodes 13S and 22S mRNAs spliced from alternative 5'SS to a common 3'SS and an independently promoted unspliced 9S mRNA.…”

Section: Introductionmentioning

confidence: 99%

The Kinetics of Synthesis of Early Viral Proteins in KB Cells Infected with Wild-type and Transformation-defective Host-range Mutants of Human Adenovirus Type 5

Rowe

Branton²,

Graham

1984

Journal of General Virology

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SUMMARYWe have studied the kinetics of early adenovirus type 5 (Ad5) protein synthesis during lytic infection of KB cells by wild-type (wt) and transformation-defective hostrange (hr) mutants. Proteins encoded within four early regions were studied: early region 1A (E1A: 1.5 to 4.5 map units, mu), E1B (4.5 to 11.2 mu), E2A (61.6 to 74-9 mu), and E4 (91.4 to 99.1 mu). Synthesis of E 1A products, the first to appear during wt lytic infection, was detectable within 2 h after injection, reached a peak within the next hour, then declined to very low levels by 7 h post-infection. Synthesis of E2 and E4 proteins began at about 3 h post-infection, was maximal by 6 h and thereafter declined sharply. The E1B 19K and 58K proteins were first detected around 3 h post-infection and, after reaching maximal levels of expression by 8 h, declined to lower levels by 12 h post-infection. Infections with the E1A mutant hr3 were characterized by greatly depressed levels of early expression of E1B, E2 and E4 polypeptides but protein synthesis from these regions appeared to recover at late times. The pattern of expression exhibited by the E1B mutant hr6 revealed delayed and reduced levels of expression of E1B, E2 and E4 protein synthesis but increased levels of E1A protein synthesis. These results are consistent with the reported role of E1A gene products in the activation of early gene expression and, in addition, suggest that a function encoded in EIB may also influence the expression of Ad5 early genes at early and late times.

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Early viral proteins in HeLa cells infected with adenovirus type 5 host range mutants

Cited by 71 publications

References 43 publications

UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells.

UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells.

Timely Synthesis of the Adenovirus Type 5 E1B 55-Kilodalton Protein Is Required for Efficient Genome Replication in Normal Human Cells

The Kinetics of Synthesis of Early Viral Proteins in KB Cells Infected with Wild-type and Transformation-defective Host-range Mutants of Human Adenovirus Type 5

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