Mouse models for generating P53 gene mutation spectra

Zielinski, Boris; Liu, Zhi-Pei; Hollstein, Monica; Hergenhahn, Manfred; Luo, Jun-Li

doi:10.1016/s0378-4274(02)00160-1

Cited by 5 publications

(5 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A direct method to induce and select TP53 mutations in mammalian cells would be to conduct a rodent cancer assay and sequence the murine TP53 gene in the carcinogen-induced tumors (Zielinski et al 2002). Although this approach has been used successfully to examine UV-induced mutations in murine skin tumors, it has limited applicability considering the unexplained paucity of TP53 mutations in most mouse tumor types other than skin.…”

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

1,726

1,321

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

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

1,726

1,321

View full text Add to dashboard Cite

show abstract

“…The utility of such studies may be limited, however, because, with the exception of skin carcinomas, the majority of chemically-induced or spontaneous tumours in mice do not necessarily contain Tp53 mutations [110]. This observation is perplexing, considering the fact that both Tp53-null mice and mice genetically engineered to express mutant Tp53 readily develop tumours.…”

Section: In Vivo Hupki Studiesmentioning

confidence: 99%

“…This observation is perplexing, considering the fact that both Tp53-null mice and mice genetically engineered to express mutant Tp53 readily develop tumours. The reason(s) for the discrepancy is still unclear, although several hypotheses have been proposed [110,111]. For example, whether or not nascent mouse Tp53 is found mutated in tumours appears to depend at least in part on the treatment protocol and target organ.…”

Section: In Vivo Hupki Studiesmentioning

confidence: 99%

Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock-in (Hupki) mouse model

Kucab

Phillips²,

Arlt³

2010

FEBS Journal

View full text Add to dashboard Cite

“…In addition to in vitro studies, the Hupki mouse can be used to study in vivo TP53 mutagenesis in carcinogen‐induced tumours [108,109]. The utility of such studies may be limited, however, because, with the exception of skin carcinomas, the majority of chemically‐induced or spontaneous tumours in mice do not necessarily contain Tp53 mutations [110]. This observation is perplexing, considering the fact that both Tp53 ‐null mice and mice genetically engineered to express mutant Tp53 readily develop tumours.…”

Section: In Vivo Hupki Studiesmentioning

confidence: 99%

“…This observation is perplexing, considering the fact that both Tp53 ‐null mice and mice genetically engineered to express mutant Tp53 readily develop tumours. The reason(s) for the discrepancy is still unclear, although several hypotheses have been proposed [110,111]. For example, whether or not nascent mouse Tp53 is found mutated in tumours appears to depend at least in part on the treatment protocol and target organ.…”

Section: In Vivo Hupki Studiesmentioning

confidence: 99%

Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock‐in (Hupki) mouse model

Kucab¹,

Phillips²,

Arlt³

2010

The FEBS Journal

View full text Add to dashboard Cite

TP53 is one of the most commonly mutated genes in human tumours. Variations in the types and frequencies of mutations at different tumour sites suggest that they may provide clues to the identity of the causative mutagenic agent. A useful model for studying human TP53 mutagenesis is the partial human TP53 knock‐in (Hupki) mouse containing exons 4–9 of human TP53 in place of the corresponding mouse exons. For an in vitro assay, embryo fibroblasts from the Hupki mouse can be examined for the generation and selection of TP53 mutations because mouse cells can be immortalized by mutation of Tp53 alone. Thus far, four environmental carcinogens have been examined using the Hupki embryo fibroblast immortalization assay: (a) UV light, which is linked to human skin cancer; (b) benzo[a]pyrene, which is associated with tobacco smoke‐induced lung cancer; (c) 3‐nitrobenzanthrone, a suspected human lung carcinogen linked to diesel exposure; and (d) aristolochic acid, which is linked to Balkan endemic nephropathy‐associated urothelial cancer. In each case, a unique TP53 mutation pattern was generated that corresponded to the pattern found in human tumours where exposure to these agents has been documented. Therefore, the Hupki embryo fibroblast immortalization assay has sufficient specificity to make it applicable to other environmental mutagens that putatively play a role in cancer aetiology. Despite the utility of the current Hupki embryo fibroblast immortalization assay, it has several limitations that could be addressed by future developments, in order to improve its sensitivity and selectivity.

show abstract

Mouse models for generating P53 gene mutation spectra

Cited by 5 publications

References 25 publications

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

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

Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock-in (Hupki) mouse model

Linking environmental carcinogen exposure to TP53 mutations in human tumours using the human TP53 knock‐in (Hupki) mouse model

Contact Info

Product

Resources

About