Genomic instability and apoptosis are frequent in p53 deficient young mice

Fukasawa, Kenji; Wiener, Francis; Woude, George F. Vande; Mai, Sabine

doi:10.1038/sj.onc.1201482

Cited by 181 publications

(152 citation statements)

References 28 publications

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“…Six (55%) of 11 G:C-to-A:T transitions occurred at CpG dinucleotides in five hot-spot codons (175, 245, 248, 273, and 282), and it was suggested that specific p53 mutations participate in the progression of human prostate cancer and may be predictive of metastasis (10). This study, in addition to some other recent studies (both in vitro and in vivo), has demonstrated correlation between loss or mutation of p53 and the presence of CI (53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). More recently, centrosome hyperamplification was found to be the major mechanism responsible for CI in vitro and in vivo (58, 59, 64 -66).…”

Section: Figure 2 P53 Ihc (Do7)supporting

confidence: 55%

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p53 Alteration and Chromosomal Instability in Prostatic High-Grade Intraepithelial Neoplasia and Concurrent Carcinoma: Analysis by Immunohistochemistry, Interphase In Situ Hybridization, and Sequencing of Laser-Captured Microdissected Specimens

et al. 2001

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p53 mutation has been shown to be associated with chromosomal instability (CI) in many human dysplastic and neoplastic lesions. However, the precise role of p53 in the pathogenesis of prostate carcinoma (Pca) is unknown. Topographic analysis of p53 alteration using immunohistochemistry (IHC) was performed on 35 archived prostatectomy specimens containing Pca foci; high-grade prostrate intraepithelial neoplasia (HPIN) foci intermingled with cancer (HPINI) and situated away (HPINA). Specimens from 2 patients were topographically genotyped using laser capture microdissection, PCR amplification, and direct sequencing of p53 exons 5-9. CI was evaluated in the same tissue foci by interphase in situ hybridization (IFISH) using centromere probes for chromosomes 7, 8, and Y. p53 immunoreactivity was found in 20%, 17%, 0, and 0 in Pca, HPINI, HPINA, and benign epithelium, respectively. p53 molecular analysis in the specimens examined confirmed the IHC findings. IFISH revealed numerical chromosomal alterations in keeping with CI in 71% and 25% of p53؉ and p53؊ Pca, respectively (P ‫؍‬ .1), 67% and 0 of p53؉ and p53؊ HPIN, respectively (P < .02), and in 27% and 0 of HPINI and HPINA, respectively. We concluded that p53 mutation is an early change in at least a subset of Pca. HPINI foci tend to have higher overall p53 immunoreactivity and CI than HPINA. The presence of p53 mutation in HPIN was associated with the presence of CI as determined by IFISH. Our study also provided additional evidence in support of the concept that HPIN might be the earliest precursor of cancer. Furthermore, our studies identify genomic similarities in HPINI and Pca, implying that carcinoma may arise from progression of certain HPIN foci that most likely harbor p53 mutation and/or more CI. KEY WORDS: Chromosomal instability, Immunohistochemistry, In situ hybridization, p53 sequencing, Prostate carcinoma, Prostate intraepithelial neoplasia.

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Section: Figure 2 P53 Ihc (Do7)supporting

confidence: 55%

“…A very strong correlation has been found between p53 loss or mutation and centrosome hyperamplification (27,55,59,67). Breast carcinoma and squamous cell carcinoma of the head and neck with either p53 deletion or mutation show centrosome hyperamplification (58,64,65).…”

Section: Figure 2 P53 Ihc (Do7)mentioning

confidence: 99%

p53 Alteration and Chromosomal Instability in Prostatic High-Grade Intraepithelial Neoplasia and Concurrent Carcinoma: Analysis by Immunohistochemistry, Interphase In Situ Hybridization, and Sequencing of Laser-Captured Microdissected Specimens

et al. 2001

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“…Activated p53 acts as a checkpoint which coordinates a shift in the pattern of gene expression involving the induction of genes which promote growth arrest or apoptosis and the repression of genes which stimulate growth or block apoptosis. In laboratory animals, the absence of p53 permits the occurrence of numerous genetic alterations, including gene ampli®cation and abnormal chromosome numbers, and leads to the development of a variety of tumours in young adults (Donehower et al, 1992;Fukasawa et al, 1997;Livinstone et al, 1992;Yin et al, 1992). These ®ndings underscore the pivotal nature of p53 in preventing tumour development and are consistent with the well established occurrence of loss of p53 function in the development of a wide range of human tumours (Hollstein et al, 1996).…”

Section: Introductionsupporting

confidence: 53%

Mechanisms of switching on p53: a role for covalent modification?

1999

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The p53 protein plays a pivotal role in activating and integrating adaptive cellular responses to a wide range of environmental stresses. Activation of p53 can occur by di erent molecular routes, depending on the nature of the activating signal. Central to the activation process, by whichever route, is the destabilization of the p53-MDM2 interaction. The molecular mechanisms which activate p53 involve elements of post-translational modi®cation, protein stabilization and protein-protein interaction. Two central themes are emerging from recent work in this area. The ®rst is that there are common events in the p53 activation process among di erent activating pathways. The second is that activation involves not just a single molecular event such as disruption of the p53-MDM2 interaction, but a series of sequential events the nature of which is governed by the type of activating stimulus. This review summarizes our current knowledge of the p53 activation process in response to two stimuli, DNA damage and activated oncogenes, and considers the contribution made by multisite phosphorylation in determining the nature of the p53 response.

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“…Previous studies have suggested that loss of p53 function is associated with chromosomal instability, favouring the development of aneuploidy, polyploidy, chromosomal breaks and ampli®cation (Bischo et al, 1990;Bou er et al, 1995;Carder et al, 1993;Donehower et al, 1995;Fukasawa et al, 1997;Harvey et al, 1993;Livingstone et al, 1992;Meling et al, 1993;Purdie et al, 1994;Tsukada et al, 1993;Yin et al, 1992). However, studies in a series of colorectal carcinoma cell lines by others, and sporadic colorectal cancers by us, suggest that, even in the presence of p53 mutation, MSI-H tumours remain chromosomal stable and near-diploid, rather than developing the multiple errors in chromosome number and structure shown typically by sporadic colorectal tumours without microsatellite instability (Eshleman et al, 1998;Curtis et al, 2000).…”

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confidence: 99%

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

et al. 2000

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We have previously reported high-frequency microsatellite instability (MSI-H) and germ-line mismatch repair gene mutation in patients with unusually young onset of high-grade glioma. Some of these patients developed metachronous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's syndrome. Frameshift mutation of TGFbRII was present in all the colorectal carcinomas but not in brain tumours. We further characterized the genetic pathways of tumour evolution in these metachronous gliomas and colorectal carcinomas. All MSI-H glioblastomas had inactivation of both alleles of the p53 gene and showed over-expression of the p53 protein while none of the colorectal carcinomas had p53 mutation or protein over-expression. Flow cytometry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable number of chromosomal arm aberrations. In contrast, the colorectal carcinomas had diploid or near-diploid DNA content with few chromosomal arm aberrations. The pattern of chromosomal aberrations in the two organs was di erent. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor ampli®cation was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its e ects di er greatly in the two organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal carcinoma, but are required for genesis of glioblastoma. Oncogene (2000) 19, 4079 ± 4083.

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Genomic instability and apoptosis are frequent in p53 deficient young mice

Cited by 181 publications

References 28 publications

p53 Alteration and Chromosomal Instability in Prostatic High-Grade Intraepithelial Neoplasia and Concurrent Carcinoma: Analysis by Immunohistochemistry, Interphase In Situ Hybridization, and Sequencing of Laser-Captured Microdissected Specimens

p53 Alteration and Chromosomal Instability in Prostatic High-Grade Intraepithelial Neoplasia and Concurrent Carcinoma: Analysis by Immunohistochemistry, Interphase In Situ Hybridization, and Sequencing of Laser-Captured Microdissected Specimens

Mechanisms of switching on p53: a role for covalent modification?

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

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