Gain of Function of a p53 Hot Spot Mutation in a Mouse Model of Li-Fraumeni Syndrome

Lang, Gene A.; Iwakuma, Tomoo; Suh, Young Ah; Li, Geng; Rao, V. Ashutosh; Parant, John M.; Valentin-Vega, Yasmine A.; Terzian, Tamara; Caldwell, Lisa; Strong, Louise C.; El‐Naggar, Adel K.; Lozano, Guillermina

doi:10.1016/j.cell.2004.11.006

Cited by 955 publications

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“…p53 mutants, which have lost their tumour suppressor capacity, are significantly capable of binding and inactivating p73 isoforms. 69,70,73 Taken together, these findings imply that mutant p53 is not only able to disrupt the function of p53 itself, but that it is also able to inhibit the apoptotic function of TAp73.…”

Section: Interplay Between P63/p73/p53 Isoformsmentioning

confidence: 78%

“…67,68 Knockin heterozygote p53 mice (p53 þ /M ) expressing one mutant p53 allele, bearing a point mutation in the DNA binding domain, are as susceptible to cancer as heterozygote p53 þ /À mice but do not show any accelerated aging phenotype. 69,70 This indicates that DNp53 proteins and point mutant p53, mutated in the DNA-binding domain, act…”

Section: Biological Activities Of P53 and Its Isoformsmentioning

confidence: 99%

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p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

2006

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Abstractp63, p73 and p53 compose a family of transcription factors involved in cell response to stress and development. p53 is the most frequently mutated gene in cancer (50%) and loss of p53 activity is considered to be ubiquitous to all cancers. Recent publications may have a profound impact on our understanding of p53 tumour suppressor activity. p63, p73 and p53 genes have a dual gene structure conserved in drosophila, zebrafish and man. They encode for multiple p63, p73 or p53 proteins containing different protein domains (isoforms) due to multiple splicing, alternative promoter and alternative initiation of translation. In this review, we describe the different isoforms of p63, p73, p53 and their roles in development and cancer. The changes in the interactions between p53, p63 and p73 isoforms are likely to be fundamental to our understanding in the transition between normal cell cycling and the onset of tumour formation. Cell Death and Differentiation (2006) Introduction p53 was discovered in 1979 as a protein interacting with the oncogenic T antigen from SV40 virus. 1-5 p53 protein is the product of a pivotal tumor-suppressor gene whose inactivation by mutation or interaction with viral or overexpressed cellular proteins occurs in almost all cancers. 6 The p53 protein integrates multiple cellular stress signals assessing cellular damages to trigger either cell-cycle arrest or programmed cell death (apoptosis). 7 These effects are predominantly due to p53's ability to bind DNA through p53-responsive element (p53RE) 8,9 and regulate the transcription of genes involved in these processes, such as p21 10 (cell cycle arrest), Puma 11 or Scotin 12 (apoptosis). Thereby, p53 prevents proliferation of genetically abnormal cells and thus cancer formation.Two p53-related genes, p63 and p73, were identified in 1997. 13,14 The high level of sequence similarity between p63, p73 and p53 proteins, particularly in the DNA binding domain, allows p63 and p73 to transactivate p53-responsive genes causing cell cycle arrest and apoptosis. Therefore, p63, p73 and p53 genes form a family of transcription factor. However, they are not functionally entirely redundant and the primary role of each p53 family member -as determined by transgenetic knockout mice -illustrates that each protein has its own unique functions.We recently published that the p53 gene family has a dual gene structure conserved from drosophila to man. 15 Like most of the genes in the human genome, 16 p53 gene family members express multiple mRNA variants due to multiple splicing and alternative promoters. Hence, p53 gene family members express different forms of p53 protein containing different domain of the protein (isoforms). In this review, we will summarise the different isoforms of p63, p73 and p53 expressed in human, mouse and drosophila. p63The mouse p63 gene is composed of 15 exons spanning over 208 000 bp (GenBank Accession Number: AF533892) on chromosome 16, while the human p63 gene is composed of 15 exons, spanning over 270 000 bp on chromosome 3q2...

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Section: Interplay Between P63/p73/p53 Isoformsmentioning

confidence: 78%

Section: Biological Activities Of P53 and Its Isoformsmentioning

confidence: 99%

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

2006

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“…We also observed an excessive doublings of Ft1 kof/kof ;p53 +/ko MEFs with respect to Ft1 +/+ ;p53 +/ko cells (Figure 6i). An increase in the proliferation rate of MEFs bearing mutation in p53 has been reported previously (Lang et al., 2004; Ma, Choudhury, Hua, Dai & Li, 2013). …”

Section: Resultsmentioning

confidence: 99%

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

et al. 2018

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SummaryHuman AKTIP and mouse Ft1 are orthologous ubiquitin E2 variant proteins involved in telomere maintenance and DNA replication. AKTIP also interacts with A‐ and B‐type lamins. These features suggest that Ft1 may be implicated in aging regulatory pathways. Here, we show that cells derived from hypomorph Ft1 mutant (Ft1 kof/kof) mice exhibit telomeric defects and that Ft1 kof/kof animals develop progeroid traits, including impaired growth, skeletal and skin defects, abnormal heart tissue, and sterility. We also demonstrate a genetic interaction between Ft1 and p53. The analysis of mice carrying mutations in both Ft1 and p53 (Ft1 kof/kof ; p53 ko/ko and Ft1 kof/kof ; p53 +/ko) showed that reduction in p53 rescues the progeroid traits of Ft1 mutants, suggesting that they are at least in part caused by a p53‐dependent DNA damage response. Conversely, Ft1 reduction alters lymphomagenesis in p53 mutant mice. These results identify Ft1 as a new player in the aging process and open the way to the analysis of its interactions with other progeria genes using the mouse model.

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“…As the allelic loss of wild-type p53 tends to occur in tumors formed in p53 heterozygous mice with a mutation on one side, [10][11][12] we examined the loss of wild-type p53 alleles in tumors developed in the mp53 mice. As determined by PCR, the wild-type p53 gene was retained in all 20 MCA-induced tumors in the mp53 mice (data not shown).…”

Section: Tumor Induction In Mp53 Transgenic Micementioning

confidence: 99%

“…Mice carrying p53 mutated at codon135 are highly sensitive to spontaneous 7,8 and chemical tumor induction. 9 Mice carrying p53 mutations analogous to the human Li-Fraumeni syndrome hot spot mutation exhibit a high incidence of spontaneous tumors with a spectrum different from that of p53-null mice, [10][11][12] a high metastatic potential for produced tumors 13 and a high incidence of chemically induced tumors. 14 Especially of note is an approach toward simulating the human context with heterozygous mice containing human p53 and Li-Fraumeni mutant p53 in the genome.…”

Section: Introductionmentioning

confidence: 99%

Mutant mouse p53 transgene elevates the chemical induction of tumors that respond to gene silencing with siRNA

Tazaki¹,

Tatsumi²,

Tsuji³

et al. 2009

Cancer Gene Ther

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To study the role of mutant p53 in the induction and cure of tumors, we generated transgenic mice carrying mutant p53 (mp53) containing a 9 bp deletion in exon 6 in addition to wild-type p53, expressing both p53 and mp53. The mp53 cDNA was cloned from a radiation-induced mouse tumor and ligated to the chicken b-actin promoter/CMV-IE enhancer in the expression vector. The presence of mp53 suppressed p21 expression in primary fibroblasts after ionizing irradiation, indicating the dominant-negative activity of mp53 in the mice. These mice developed fibrosarcomas after the subcutaneous injection of 3-methylcholanthrene with an incidence 1.7-fold higher than that of wild-type mice (42% excess). The tumors were then treated via a potent atelocollagen delivery system with small interfering RNA (siRNA), that targeted the promoter/enhancer of the expression vector, resulting in the suppression of tumor growth in 30% of 44 autochthonous tumors, including four cures, and their transplants, the total fraction corresponding to the tumor excess. This suppressive effect involved the induction of apoptosis. These results indicate that mp53 activity causes tumors that can be suppressed by subsequent silencing of mp53 in the presence of wild-type p53 alleles.

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Gain of Function of a p53 Hot Spot Mutation in a Mouse Model of Li-Fraumeni Syndrome

Cited by 955 publications

References 53 publications

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

Mutant mouse p53 transgene elevates the chemical induction of tumors that respond to gene silencing with siRNA

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