High-frequency developmental abnormalities in p53-deficient mice

Armstrong, Jane F.; Kaufman, M. H.; Harrison, David J.; Clarke, Alan R.

doi:10.1016/s0960-9822(95)00183-7

Cited by 420 publications

(352 citation statements)

References 13 publications

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“…Furthermore, the Pin1À/Àp53À/À mice had shorter life spans than the p53À/Àmice. p53À/À females are known to display exencephaly (Armstrong et al, 1995;Sah et al, 1995), and in the present study Pin1À/Àp53À/À female embryos displayed exencephaly to a greater extent than p53À/À female embryos. Thus, Pin1 may prevent p53-deficient mice from developing female-specific exencephaly.…”

Section: Discussionsupporting

confidence: 63%

“…Although p53-deficient mice survive birth they rapidly succumb to tumors, predominantly of the thymic lymphoid lineages (Donehower et al, 1992;Jacks et al, 1994;Purdie et al, 1994). There have also been reports of high-frequency embryonic lethality derived from female-specific developmental abnormalities, namely neural tube-closure failure leading to exencephaly and subsequent anencephaly (Armstrong et al, 1995;Sah et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1

et al. 2006

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Tumor suppressor p53 is essential for checkpoint control in response to a variety of genotoxic stresses. DNA damage leads to phosphorylation on the Ser/Thr-Pro motifs of p53, which facilitates interaction with Pin1, a pSer/pThr-Prospecific peptidyl prolyl isomerase. Pin1 is required for the timely activation of p53, resulting in apoptosis or cell cycle arrest. To investigate the physiological relationship between Pin1 and p53, we created Pin1À/Àp53À/À mice. These p53-deficient mice spontaneously developed lymphomas, mainly of thymic origin, as well as generalized lymphoma infiltration into other organs, including the liver, kidneys and lungs. Ablation of Pin1, in addition to p53, accelerated the thymic hyperplasia, but the thymocytes in these Pin1À/À p53À/À mice did not infiltrate other organs. The thymocytes in 12-week-old Pin1À/Àp53À/À mice were CD4 À CD8 À (double negative) and had significantly higher levels of the intracellular form of Notch1 (NIC) than the thymocytes of p53À/À or wild-type mice. Presenilin-1, a cleavage enzyme for NIC generation from full-length Notch1 was increased in the thymocytes of Pin1À/Àp53À/À mice. Pin1 depletion also inhibited the degradation of NIC by proteasomes. These results suggest that both Pin1 and p53 control the normal proliferation and differentiation of thymocytes by regulating the NIC level.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1

et al. 2006

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“…In contrast to the situation in homozygous null mice in which 100% had developed tumours or died by 10 months of age, only 50% of heterozygotes had developed tumours by the age of 18 months. The spectrum of tumours differed between the two groups, with 58% of the heterozygotes developing sarcomas (predominantly osteosarcomas) and only 32% developing lymphomas (Harvey et al, 1993) (Armstrong et al, 1995;Sah et al, 1995).…”

Section: Animal Models Of Li-fraumeni Syndromementioning

confidence: 96%

Li-Fraumeni syndrome – a molecular and clinical review

Varley

Evans²,

Birch³

1997

Br J Cancer

318

180

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“…These defects may arise either because p53 plays a physiological role at the time of neural tube closure or because of an abnormally high frequency of mutation within the haploid gametes of p53-null parents. 65,66 Knockin heterozygote p53 mice (p53 þ /DNp53 ) expressing amino-truncated p53 proteins are less susceptible to cancer than heterozygote p53 þ /À mice but develop concomitant accelerated aging phenotype. Knockin homozygote mice (p53 DNp53/DNp53 ), expressing only amino-truncated p53 proteins, are cancer-prone like p53 À/À mice, and do not show any accelerated aging phenotype, indicating that that is dependent on the effect in trans of DNp53 on wild-type p53.…”

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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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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High-frequency developmental abnormalities in p53-deficient mice

Cited by 420 publications

References 13 publications

Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1

Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1

Li-Fraumeni syndrome – a molecular and clinical review

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

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