Host cell reactivation of gamma-irradiated adenovirus 5 in human cell lines of varying radiosensitivity

Eady, John J.; Peacock, John; McMillan, Trevor J.

doi:10.1038/bjc.1992.226

Cited by 15 publications

(5 citation statements)

References 33 publications

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“…Moreover, the phenomenon of induced radioresistance has been earlier described in human lymphocytes 27 and in some other human cells. 23,28,29 In these studies, the exposure to an initial radiation dose before subsequent doses has been shown to result in a higher resistance. This has been assumed to be an evidence of cellular radioprotective mechanisms that are triggered in response to exposure to small doses of ionizing radiation.…”

Section: Discussionmentioning

confidence: 99%

Sublethal damage repair capacity in carcinoma cell lines with p53 mutations

et al. 1998

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Section: Discussionmentioning

confidence: 99%

Sublethal damage repair capacity in carcinoma cell lines with p53 mutations

et al. 1998

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“…Clinically, it is well established that NB tumors are highly radiosensitive, making radiotherapy a major treatment modality (18,27). Likewise, undifferentiated human NB cell lines are unusually radiosensitive (8,23,33,37). In fact, high UV radiation sensitivity of NB cells was associated with very low DNA repair activity.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Sequestration of Wild-Type p53 Protein Impairs the G₁ Checkpoint after DNA Damage

Moll

Ostermeyer

Haladay

et al. 1996

Molecular and Cellular Biology

259

234

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. This may represent a nonmutational mechanism for abrogating p53 tumor suppressor function. To test this hypothesis, we established the first available in vitro model that accurately reflects the wild-type p53 sequestration found in NB tumors. We characterized a series of human NB cell lines that overexpress wild-type p53 and show that p53 is preferentially localized to discrete cytoplasmic structures, with no detectable nuclear p53. These cell lines, when challenged with a variety of DNA strand-breaking agents, all exhibit impaired p53-mediated G 1 arrest. Induction analysis of p53 and p53-responsive genes show that this impairment is due to suppression of nuclear p53 accumulation. Thus, this naturally occurring translocation defect compromises the suppressor function of p53 and likely plays a role in the tumorigenesis of these tumors previously thought to be unaffected by p53 alterations.Wild-type p53 plays a key suppressor role in cell growth and tumor formation. p53 acts as a cell cycle checkpoint after DNA damage, induces G 1 arrest or apoptosis (reviewed in reference 63), and is required to maintain genomic stability (34, 70). The mechanism underlying its central growth suppression is largely based on p53's function as a potent transcriptional regulator (9, 13) of crucial growth-inhibitory genes such as Waf-1, a universal inhibitor of cyclin kinase complexes (10,19,47,67). The domain structure of p53 reveals an N-terminal transactivation region, a central sequence-specific DNA-binding region, and a C-terminal oligomerization region that also harbors several nuclear localization domains (reviewed in reference 50). Accordingly, p53 is a nuclear phosphoprotein, and nuclear localization is essential for its growth-suppressing activity in late G 1 (14,15,(53)(54)(55)(56). Site-directed mutagenesis of the primary nuclear localization signal (at residues 316 to 322) caused cytoplasmic retention and completely destroyed the transformation-suppressing activity of wild-type p53 (56). In normal cells, p53 levels are tightly regulated as a result of a short half-life of 15 to 30 min (49) and are not detectable by immunocytochemistry (31).Disruption of the p53 response pathway strongly correlates with tumorigenesis. Indeed, functional inactivation of p53 is the single most common event in human malignancies and occurs in at least 50% of all cancers (20). Mutational inactivation is the most common mechanism and occurs in a large spectrum of sporadic and familial cancers of, e.g., the breast, gastrointestinal tract, lung, brain, and soft tissues (22). Deletion of one allele accompanied by a missense mutation in the central DNA-binding domain of the remaining allele is classical. Most point mutations prolong the half-life of p53, leading to nuclear accumulation which now becomes readily detectable by immunocytochemistry. Though less frequent, mutation-independent mechanisms are also utilized in human malignancies. Here, the common theme is sequestration of wild-type p53 protein by another protein which abrogates its supp...

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“…[46,47]). Other reports have found no evidence that A‐T cells are functionally defective in DNA repair [48,49]. On the other hand, A‐T homozygotes may have subtle defects in their ability to process DNA breaks, as the accuracy of strand rejoining appears to be impaired in A‐T cells [50,51].…”

Section: Ataxia‐telangiectasiamentioning

confidence: 97%

Ataxia‐telangiectasia, cancer and the pathobiology of the ATM gene

1999

Clinical Genetics

203

147

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Ataxia-telangiectasia (A-T) is a pleiotropic inherited disease characterized by neurodegeneration, cancer, immunodeficiencies, radiation sensitivity, and genetic instability. Although A-T homozygotes are rare, the A-T gene may play a role in sporadic breast cancer and leukemia. ATM, the gene responsible for A-T, is homologous to several cell cycle checkpoint genes from other organisms. ATM is thought to play a crucial role in a signal transduction network that modulates cell cycle checkpoints, genetic recombination, apoptosis, and other cellular responses to DNA damage. New insights into the pathobiology of A-T have been provided by the creation of Atm-/- mice and by in vitro studies of ATM function. Analyses of ATM mutations in A-T patients and in sporadic tumors suggest the existence of two classes of ATM mutation: null mutations that lead to A-T and dominant negative missense mutations that may predispose to cancer in the heterozygous state.

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Host cell reactivation of gamma-irradiated adenovirus 5 in human cell lines of varying radiosensitivity

Cited by 15 publications

References 33 publications

Sublethal damage repair capacity in carcinoma cell lines with p53 mutations

Sublethal damage repair capacity in carcinoma cell lines with p53 mutations

Cytoplasmic Sequestration of Wild-Type p53 Protein Impairs the G₁ Checkpoint after DNA Damage

Ataxia‐telangiectasia, cancer and the pathobiology of the ATM gene

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Host cell reactivation of gamma-irradiated adenovirus 5 in human cell lines of varying radiosensitivity

Cited by 15 publications

References 33 publications

Sublethal damage repair capacity in carcinoma cell lines with p53 mutations

Sublethal damage repair capacity in carcinoma cell lines with p53 mutations

Cytoplasmic Sequestration of Wild-Type p53 Protein Impairs the G1 Checkpoint after DNA Damage

Ataxia‐telangiectasia, cancer and the pathobiology of the ATM gene

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Product

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Cytoplasmic Sequestration of Wild-Type p53 Protein Impairs the G₁ Checkpoint after DNA Damage