Common tumour p53 mutations in immortalized cells from Hupki mice heterozygous at codon 72

Reinbold, Manuela; Jl, Luo; Nedelko, Tatiana; Jerchow, Boris; Murphy, Maureen E.; Whibley, Catherine; Qin, Wei; Hollstein, Monica

doi:10.1038/sj.onc.1210932

Cited by 39 publications

(75 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…TP53 'signature mutations' obtained using this approach revealed a remarkable degree of concordance between mutations that allow senescence bypass in vitro and mutations that arise in vivo. 51 Overall, these data show that the origin of TP53 mutations is greatly influenced by cancer-initiating events such as DNA-damage stress and that the effect of these mutations is to promote cancer development through loss of antiproliferative activities including apoptosis and senescence.…”

Section: P53 and Molecular Carcinogenesismentioning

confidence: 97%

“…They showed that the oncogene-induced DNA-damage response is activated according to a threshold that correlates with the risk of invasive carcinoma, leading to a selection pressure that inactivates the proteins involved in both checkpoint and repair processes during early stages of tumor development, such as p53. Using the humanized p53 gene knock-in (Hupki) mouse model, Reinbold et al 51 studied the role of environmental mutagenesis in senescence bypass. In mice, senescence control is regulated by the p19ARF/p53 pathway, and escape from this control can occur through TP53 inactivation by point mutation.…”

Section: P53 and Molecular Carcinogenesismentioning

confidence: 99%

See 1 more Smart Citation

Recent advances in p53 research: an interdisciplinary perspective

et al. 2008

View full text Add to dashboard Cite

The TP53 gene is one of the most studied genes in human cancer. In recent years, considerable interest was focused on mutant p53, the abnormal protein product of TP53 somatic or germline alleles with missense mutations that often accumulate in cancer cells. There is now compelling experimental evidence that many mutations can exert mutant-specific, gain-of-function effects by perturbing the regulation of expression of multiple genes. This notion is supported by the observation that targeted mutant p53 expression enhances the formation of specific cancers in the mouse even in the absence of wild-type p53 expression. In addition, clinical studies are producing a wealth of functional pathway data demonstrating correlations between specific TP53 mutations and gene expression patterns identified by transcriptome studies. These correlations imply that alteration of p53 function is critical in shaping gene expression patterns in cancer. Finally, progress is being made in the development of new therapeutic approaches targeting p53 alterations. Key advances regarding the structural, biochemical and functional properties of normal and mutant p53 proteins, their abnormal regulation and distribution in human cancers, and their associations with clinical and pathological cancer characteristics are reviewed. New opportunities for translational research for improving cancer detection, prognosis, prevention and therapy based upon the integration of this knowledge are described.

show abstract

Section: P53 and Molecular Carcinogenesismentioning

confidence: 97%

Section: P53 and Molecular Carcinogenesismentioning

confidence: 99%

Recent advances in p53 research: an interdisciplinary perspective

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The HUF Assay (Hupki fibroblast assay) is a novel mutagenesis test in primary cells from "humanized" mice that was designed to circumvent the difficulties discussed above . HupKi (Human p53-Knockin) mice harbor human TP53 sequences encoding both the polyproline and the DNA binding domain, where most human tumor mutations arise (Luo et al 2001;Reinbold et al 2008), replacing the homologous murine gene segments within the mouse TP53 locus. Hupki p53 is functional and regulated normally in mice.…”

Section: Experimental Systemsmentioning

confidence: 99%

TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use

Olivier¹,

Hollstein²,

Hainaut³

2009

Cold Spring Harbor Perspectives in Biology

1,581

1,255

View full text Add to dashboard Cite

Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers, and germline mutations are the underlying cause of Li-Fraumeni syndrome, which predisposes to a wide spectrum of early-onset cancers. Most mutations are single-base substitutions distributed throughout the coding sequence. Their diverse types and positions may inform on the nature of mutagenic mechanisms involved in cancer etiology. TP53 mutations are also potential prognostic and predictive markers, as well as targets for pharmacological intervention. All mutations found in human cancers are compiled in the IARC TP53 Database (http://www-p53.iarc.fr/). A human TP53 knockin mouse model (Hupki mouse) provides an experimental model to study mutagenesis in the context of a human TP53 sequence. Here, we summarize current knowledge on TP53 gene variations observed in human cancers and populations, and current clinical applications derived from this knowledge.

show abstract

“…There are 2 Hupki strains that have wild-type human p53 sequences, one with the codon 72 (in exon 4) encoding arginine and one encoding proline. 19,20 In both strains the chimeric human-mouse p53 protein is functional and tumor suppressive. 8,[19][20][21] In analyzing the DNA damage response of inbred Hupki P72 and R72 mice, we noted that the P72 allele was consistently able to induce 2.5-fold increased apoptosis in the thymus, compared to R72.…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific apoptotic effects of the p53 codon 72 polymorphism in a mouse model

Azzam¹,

Frank²,

Hollstein³

et al. 2011

Cell Cycle

View full text Add to dashboard Cite

Currently there are several dozen human polymorphisms that have been loosely associated with cancer risk. Correlating such variants with cancer risk has been challenging, primarily due to factors such as genetic heterogeneity, contributions of diet and environmental factors, and the difficulty in obtaining large sample sizes for analysis. Such difficulties can be circumvented with the establishment of mouse models for human variants. Recently, several groups have modeled human cancer susceptibility polymorphisms in the mouse. Remarkably, in each case these mouse models have accurately reflected human phenotypes, and clarified the contribution of these variants to cancer risk. We recently reported on a mouse model for the codon 72 polymorphism in p53, and found that this polymorphism regulates the ability to cooperate with NFκB and induce apoptosis. Here-in we present evidence that this polymorphism impacts the apoptotic function of p53 in a tissue-specific manner; such tissue-specific effects of polymorphic variants represent an added challenge to human cancer risk association studies. The data presented here support the premise that modeling human polymorphisms in the mouse represents a powerful tool to assess the impact of these variants on cancer risk, progression and therapy.

show abstract

Common tumour p53 mutations in immortalized cells from Hupki mice heterozygous at codon 72

Cited by 39 publications

References 28 publications

Recent advances in p53 research: an interdisciplinary perspective

Recent advances in p53 research: an interdisciplinary perspective

TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use

Tissue-specific apoptotic effects of the p53 codon 72 polymorphism in a mouse model

Contact Info

Product

Resources

About