p53 Checkpoint-Defective Cells Are Sensitive to X Rays, but Not Hypoxia

Denko, Nicholas C.; Green, Susannah L.; Edwards, Diana; Giaccia, Amato J.

doi:10.1006/excr.2000.4928

Cited by 21 publications

(13 citation statements)

References 30 publications

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“…Normal cellular proteins that bind to p53 in a manner similar to viral oncoproteins have been identified and found to be potential oncogenes (Nees et al, 2001). Alternatively, increased p53 protein expression might be representative of progressive chromosomal damage, such as cells treated in vitro with ultraviolet or gamma irradiation (Zhang et al, 1993;Agami and Bernards, 2000;Denko et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

Pardo

Hsu

Zeheb³

et al. 2004

Br J Cancer

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Abnormalities of the p53 tumor-suppressor gene are found in a significant proportion of astrocytic brain tumours. We studied tumour specimens from 74 patients evaluated over 20 years at the Massachusetts General Hospital, where clinical outcome could be determined and sufficient pathologic material was available for immunostaining. p53 expression studies employed an affinity-purified p53 monoclonal antibody, whose specificity was verified in absorption studies and, in a minority of cases, a second antibody recognising a different epitope of p53. Significant overexpression of p53 protein was found in 48% of the 74 tumours included in this series and high levels of expression were associated with higher mortality from astrocytic tumours (Po0.001, log rank). Multivariate analyses revealed that immunohistochemically detected p53 was an independent marker of shortened progression-free and overall actuarial survival in patients with astrocytic tumours, suggesting that increased expression of p53 plays an important role in the pathobiology of these tumours. In a subset of 36 cases, coding regions of the p53 gene were completely sequenced via SSCP and direct DNA sequencing, revealing that overexpression of p53 protein is not always associated with point mutations in conserved exons of the p53 gene. Finally, we confirmed p53 protein expression in early-passage human glioma cell lines of known p53 mutational status and immunostaining scores. Although grade continues to be the strongest prognostic variable, the use of p53 staining as a prognostic indicator, in contrast to mutational DNA analyses, may be a useful adjunct in identifying patients at higher risk of treatment failure.

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Section: Discussionmentioning

confidence: 99%

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

Pardo

Hsu

Zeheb³

et al. 2004

Br J Cancer

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“…This could explain the p21 induction caused by reoxygenation, which is known to lead to free radical production and can be considered a stress in itself. In addition, the p21 message, but not protein, is induced in a p53-independent manner under hypoxia in a variety of cell lines (10), and reoxygenation may allow translation of this accumulated mRNA.…”

Section: Discussionmentioning

confidence: 99%

p21^Cip1 and p27^Kip1Regulate Cell Cycle Reentry after Hypoxic Stress but Are Not Necessary for Hypoxia-Induced Arrest

Green

Freiberg

Giaccia

2001

Molecular and Cellular Biology

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101

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We investigated the role of the cyclin-dependent kinase inhibitors p21Cip1 and p27 Kip1 in cell cycle regulation during hypoxia and reoxygenation. While moderate hypoxia (1 or 0.1% oxygen) does not significantly impair bromodeoxyuridine incorporation, at very low oxygen tensions (0.01% oxygen) DNA replication is rapidly shut down in immortalized mouse embryo fibroblasts. This S-phase arrest is intact in fibroblasts lacking the cyclin kinase inhibitors p21Cip1 and p27 Kip1 , indicating that these molecules are not essential elements of the arrest pathway. Hypoxia-induced arrest is accompanied by dephosphorylation of pRb and inhibition of cyclindependent kinase 2, which results in part from inhibitory phosphorylation. Interestingly, cells lacking the retinoblastoma tumor suppressor protein also display arrest under hypoxia, suggesting that pRb is not an essential mediator of this response. Upon reoxygenation, DNA synthesis resumes by 3.5 h and reaches aerobic levels by 6 h. Cells lacking p21, however, resume DNA synthesis more rapidly upon reoxygenation than wild-type cells, suggesting that this inhibitor may play a role in preventing premature reentry into the cell cycle upon cessation of the hypoxic stress. While p27 null cells did not exhibit rapid reentry into the cell cycle, cells lacking both p21 and p27 entered S phase even more aggressively than those lacking p21 alone, revealing a possible secondary role for p27 in this response. Cdk2 activity is also restored more rapidly in the doubleknockout cells when returned to normoxia. These studies reveal that restoration of DNA synthesis after hypoxic stress, but not the S phase arrest itself, is regulated by p21 and p27.

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“…25, 26, 38 The induction of p21 by hypoxia is also used in some reports to suggest a p53-transactivating activity 9, 39 but it is important to note that p21 has also been described to be induced by hypoxia in a p53-independent manner. 40 …”

Section: Effects Of Hypoxia On P53 Protein Level and Activitymentioning

confidence: 99%

Reciprocal influence of the p53 and the hypoxic pathways

2011

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When cells sense a decrease in oxygen availability (hypoxia), they develop adaptive responses in order to sustain this condition and survive. If hypoxia lasts too long or is too severe, the cells eventually die. Hypoxia is also known to modulate the p53 pathway, in a manner dependent or not of HIF-1 (hypoxia-inducible factor-1), the main transcription factor activated by hypoxia. The p53 protein is a transcription factor, which is rapidly stabilised by cellular stresses and which has a major role in the cell responses to these stresses. The aim of this review is to compile what has been reported until now about the interconnection between these two important pathways. Indeed, according to the cell line, the severity and the duration of hypoxia, oxygen deficiency influences very differently p53 protein level and activity. Conversely, p53 is also described to affect HIF-1α stability, one of the two subunits of HIF-1, and HIF-1 activity. The direct and indirect interactions between HIF-1α and p53 are described as well as the involvement in this complex network of their respective ubiquitin ligases von Hippel Lindau protein and murine double minute 2. Finally, the synergistic or antagonistic effects of p53 and HIF-1 on some important cellular pathways are discussed.

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p53 Checkpoint-Defective Cells Are Sensitive to X Rays, but Not Hypoxia

Cited by 21 publications

References 30 publications

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

p21^Cip1 and p27^Kip1Regulate Cell Cycle Reentry after Hypoxic Stress but Are Not Necessary for Hypoxia-Induced Arrest

Reciprocal influence of the p53 and the hypoxic pathways

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p53 Checkpoint-Defective Cells Are Sensitive to X Rays, but Not Hypoxia

Cited by 21 publications

References 30 publications

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumours of astrocytic lineage

p21Cip1 and p27Kip1Regulate Cell Cycle Reentry after Hypoxic Stress but Are Not Necessary for Hypoxia-Induced Arrest

Reciprocal influence of the p53 and the hypoxic pathways

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About

p21^Cip1 and p27^Kip1Regulate Cell Cycle Reentry after Hypoxic Stress but Are Not Necessary for Hypoxia-Induced Arrest