p53, guardian of the genome

Lane, David P.

doi:10.1038/358015a0

Cited by 4,653 publications

(2,618 citation statements)

References 17 publications

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“…The tumor suppressor gene p53 is viewed as the guardian of the genome (Lane, 1992) which regulates the cellular response to various stress signals, most notably exogenous DNA damage. In unstressed cells, p53 appears to be present at low levels and is assumed to exist in a latent form that requires modi®cation to become active (Giaccia and Kastan, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Activated p53 acts as a transcription factor that up-regulates several downstream genes. In many cell types, the dominant cellular response pathway is the G1 cell cycle arrest which is mediated by up-regulation of p21 (Kastan et al, 1992;El-Deiry et al, 1993) and which is assumed to allow for adequate repair of damaged DNA before entering S phase (Lane, 1992;Sherr, 1996). In certain cell types and situations, p53 can alternatively trigger apoptosis (Ko and Prives, 1996;Sherr, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control

et al. 2000

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The tumor suppressor p53 is considered as the guardian of the genome which is activated following genotoxic stress. In many cell types, p53 mediates G1 cell cycle arrest as the predominant cellular response. Inactivation of wild-type p53 leads to loss of G1/S checkpoint control and to genomic instability, including increased spontaneous homologous recombination (HR). To determine whether regulation of the G1/S checkpoint is required for suppression of HR, we assessed recombination events using a plasmid substrate that stably integrated into the genome of p53-null mouse ®broblasts. Exogenous expression of a temperature-sensitive p53 protein (Ala135 to Val), which had lost trans-activation function and could not regulate G1/S transition when in mutant conformation, reduced HR rates to the same extent as wild-type p53. Furthermore, a p53 construct with an alternatively-spliced carboxy terminus also retained this ability in the absence of both activities, G1/S control and non-sequence speci®c DNA binding as mediated by the carboxy terminus. Our data dissociate regulation of HR by p53 from its role as a cell cycle checkpoint protein.The results support a model which extends p53's role as a guardian of the genome to include transactivationindependent regulatory functions in DNA repair, replication and recombination. Oncogene (2000) 19, 632 ± 639.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control

et al. 2000

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“…Indeed, the p53 gene is one of the most frequently mutated genes in human malignancies (Hollstein et al, 1991;Levine et al, 1991;Vogelstein and Kinzler, 1992). Its product, the wild-type (WT) p53 protein, plays an important role in the cellular response to DNA damage by controlling cell cycle and allowing repair of the altered genome (Hartwell, 1992;Lane, 1992). The responses of the p53-dependent signaling pathways to di erent stresses such as anticancer drugs or irradiations have been extensively studied.…”

Section: Introductionmentioning

confidence: 99%

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

et al. 2000

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The tumor suppressor p53 plays a pivotal role in the cellular response to DNA damage as it controls DNA repair, cell cycle arrest and apoptosis. We studied the autoregulation of human p53 gene transcription in colon cancer cell lines. Wild-type p53 has been shown to autoregulate its own transcription either positively or negatively and probably in a cell-type-speci®c manner. Indeed, a p53 binding site has been described in the human and murine p53 promoters, but a direct binding of wild-type p53 protein to this site has never been reported.In this study, we demonstrated a transactivation of human p53 promoter by wild-type p53 in human colon cancer cells. We identi®ed in the human p53 promoter a novel potential p53-responsive element that binds wildtype p53. Moreover, wild-type p53 protein transactivated a reporter plasmid containing a luciferase gene driven by a minimal promoter harboring this p53 binding site. Finally, as the p53 promoter contains an NF-kB binding site, we demonstrated an additive e ect when NF-kB subunits and p53 protein combined to transactivate the human p53 promoter. Oncogene (2000) 19, 4787 ± 4794.

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“…Mdm2 is an oncogene that exerts negative feedback on p53 (Momand et al, 1992;, WAF1/Cipl is an inhibitor of cyclin-dependent kinases (El-Deiry et al, 1993;Harper et al, 1993) and Gadd45 is capable of blocking progression through the cell cycle in GI, a process reversible by mdm2 (Levine et al, 1994). p53 also controls the cell cycle as 'guardian of the genome' (Lane, 1992), and in UV-damaged skin it is considered 'guardian of the tissue ' (Ziegler et al, 1994) inducing apoptosis in sunburn cells.…”

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confidence: 99%

A non-random deletion in the p53 gene in oral squamous cell carcinoma

Nylander

Schildt²,

Magnusson³

et al. 1996

Br J Cancer

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Summary In a retrospective study of the mutational spectrum of the p53 gene in oral squamous cell carcinoma, 80 primary tumours diagnosed in 1980-90 were included. Using polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) analysis 47 mutations were found distributed in 39 of the tumours (49%). Unexpectedly, the majority of the mutations (29/47; 62%) were found in exon 8, and at sequencing 17 of them showed a 14 bp deletion in codons 287-292, causing formation of a stop codon and accordingly a truncated protein lacking the C-terminal. The majority of the patients with the 14 bp deletion were women (13/17), and it seemed as though certain potential risk factors for carcinoma of the head and neck were less common in this group.

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p53, guardian of the genome

Cited by 4,653 publications

References 17 publications

Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control

Dissociation of p53-mediated suppression of homologous recombination from G1/S cell cycle checkpoint control

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

A non-random deletion in the p53 gene in oral squamous cell carcinoma

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