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Query: UNIPROT:P06889 (Mol)
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Mice with disrupted germline p53 alleles have been engineered by us and others and have been shown to have enhanced susceptibility to spontaneous tumors of various types. We monitored a large number of p53-deficient mice (p53+/- and p53-/-) and their wild-type littermates (p53+/+) of two different genetic backgrounds (129/Sv and mixed C57BL/6 x 129/Sv) up to 2 yr of age. p53+/- and p53-/- 129/Sv mice show accelerated tumorigenesis rates compared with their p53-deficient counterparts of mixed C57BL/6 x 129/Sv genetic background. The tumor spectra of the two strains of mice are similar except that almost half of 129/Sv p53-/- males develop malignant teratomas, whereas these tumors are rarely observed in C57BL/6 x 129/Sv mice and never in 129/Sv p53+/- males. In the study reported here, we further characterized the lymphomas that arose in the p53-nullizygous mice and found that over three-quarters of the lymphomas were of thymic origin and contained primarily immature (CD4+/CD8+) T-cells, whereas the remainder originated in the spleen and peripheral lymph nodes and were of B-cell type. The high incidence of early-onset lymphomas in the nullizygous mice makes these animals a good lymphoma model, whereas the heterozygous mice may be a useful model for Li-Fraumeni syndrome, a human inherited cancer predisposition.
Mol Carcinog 1995 Sep
PMID:Effects of genetic background on tumorigenesis in p53-deficient mice. 754 19

A mutation in the tumor suppressor p53 gene resulting in an Arg-->Ser substitution in position 249 is found frequently in human hepatocellular carcinomas associated with hepatitis B infection and with aflatoxin exposure. To determine the significance of this mutation in an in vivo experimental model using transgenic mice, we introduced a two-nucleotide change in the mouse p53 gene at amino-acid position 246, which is equivalent to position 249 in human p53, by the recombinant polymerase chain reaction mismatched primer method. This p53 mutation resulted in the same change, an Arg-->Ser substitution, as in the human p53 gene at position 249. We now report that the protein product of this mutant mouse p53ser246 had properties similar to those of the wild-type protein when tested by binding to (i) monoclonal antibodies PAb246 and PAb240, ii) simian virus 40 large T antigen, and (iii) heat-shock protein. However, it had mutant-type transforming properties when tested for colony formation with an osteosarcoma cell line. It was not active, as is wild-type p53, in transcription activation of the muscle creatine kinase promoter. These properties are the same as those found in the p53trp248 product of the p53 mutation associated with the Li-Fraumeni syndrome. Although less is known about the human p53ser249 product associated with hepatocellular carcinoma, the mutant murine p53ser246 protein shares the known properties of the human gene product.
Mol Carcinog 1995 Jun
PMID:Characterization of a murine p53ser246 mutant equivalent to the human p53ser249 associated with hepatocellular carcinoma and aflatoxin exposure. 760 78

Normal cells have a strictly limited growth potential and senesce after a defined number of population doublings (PDs). In contrast, tumor cells often exhibit an apparently unlimited proliferative potential and are termed immortalized. Although spontaneous immortalization of normal human cells in vitro is an extremely rare event, we observed this in fibroblasts from an affected member of a Li-Fraumeni syndrome kindred. The fibroblasts were heterozygous for a p53 mutation and underwent senescence as expected at PD 40. In four separate senescent cultures (A to D), there were cells that eventually recommenced proliferation. This was associated with aneuploidy in all four cultures and either loss (cultures A, C, and D) or mutation (culture B) of the wild-type (wt) p53 allele. Loss of wt p53 function was insufficient for immortalization, since cultures A, B, and D subsequently entered crisis from which they did not escape. Culture C has continued proliferating beyond 400 PDs and thus appears to be immortalized. In contrast to the other cultures, the immortalized cells have no detectable p16INK4 protein. A culture that had a limited extension of proliferative potential exhibited a progressive decrease in telomere length with increasing PD. In the culture that subsequently became immortalized, the same trend occurred until PD 73, after which there was a significant increase in the amount of telomeric DNA, despite the absence of telomerase activity. Immortalization of these cells thus appears to be associated with loss of wt p53 and p16INK4 expression and a novel mechanism for the elongation of telomeres.
Mol Cell Biol 1995 Sep
PMID:Alterations in p53 and p16INK4 expression and telomere length during spontaneous immortalization of Li-Fraumeni syndrome fibroblasts. 765 92

Individuals with germ line mutations in the p53 gene, such as Li-Fraumeni syndrome (LFS), have an increased occurrence of many types of cancer, including an unusually high incidence of breast cancer. This report documents that normal breast epithelial cells obtained from a patient with LFS (with a mutation at codon 133 of the p53 gene) spontaneously immortalized in cell culture while the breast stromal fibroblasts from this same patient did not. Spontaneous immortalization of human cells in vitro is an extremely rare event. This is the first documented case of the spontaneous immortalization of breast epithelial cells from a patient with LFS in culture. LFS patient breast stromal fibroblasts infected with a retroviral vector containing human papillomavirus type 16 E7 alone were able to immortalize, whereas stromal cells obtained from patients with wild-type p53, similarly infected with human papillomavirus type 16 E7, did not. The present results indicate a protective role of normal pRb-like functions in breast stromal fibroblasts but not in breast epithelial cells and reinforces an important role of wild-type p53 in the regulation of the normal growth and development of breast epithelial tissue.
Mol Cell Biol 1995 Jan
PMID:Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome. 779 51

The p53 tumor suppressor gene is the most commonly altered gene in human cancers. Germline mutations in p53 are the genetic alteration underlying predisposition to multiple cancers in Li-Fraumeni syndrome and Li-Fraumeni-like syndrome. We describe a patient who presented with developed adrenocortical carcinoma at age 19 months and a cerebral primitive neuroectodermal tumor at age 5 years. The patient did not have a family history of cancer. We used the enzyme mismatch cleavage (EMC) method to screen for mutations in the p53 gene and found a germline mutation in exon 7 (codon 248). Loss of heterozygosity analysis in one tumor revealed loss of the wild-type p53 allele. In our report we demonstrate the EMC method to be a rapid and sensitive method for mutation detection.
Diagn Mol Pathol 1996 Dec
PMID:Rapid diagnosis of germline p53 mutation using the enzyme mismatch cleavage method. 895 18

We identified four families in which we suspected the presence of genetic factors predisposing them to cancer. We examined one family with features suggesting Li-Fraumeni syndrome for the presence of a germline p53 mutation in 13 of its members. To detect germline p53 mutations we performed polymerase chain reaction/nonradioisotopic single-strand conformation polymorphism and DNA sequencing analysis on exons 4-9 of the p53 gene. Mutated polymerase chain reaction-restriction fragment length polymorphism analysis was also performed on exon 5 to confirm the mutation identified by the sequencing analysis. A novel germline p53 mutation was identified at codon 133 (ATG-->AGG) in exon 5, resulting in the substitution of arginine for methionine, in all four cancer-affected individuals and in three apparently healthy individuals. We also analyzed tumor specimens for additional p53 mutations in the wild-type alleles using the same methods. However, heterozygosity was retained, and no other additional mutations in the wild-type allele were identified in any of the tumor tissues. It is possible that additional mutations in the wild-type allele are not always necessary for the loss of tumor suppressor functions. This study presents serious clinical and ethical problems about the predictive value of identifying germline p53 mutations in presymptomatic carriers. However, accurate predictive testing will be very useful in identifying unaffected individuals who are at increased risk of developing cancer and in detecting cancer at an early stage.
J Mol Med (Berl) 1997 Jan
PMID:Germline p53 mutation at codon 133 in a cancer-prone family. 902 Mar 84

The induction of immortalization of human fibroblasts by carcinogens is a very rare process. Hybrids between immortal cells and normal fibroblasts senesce, indicating that immortal cells must lose one or more senescence genes for immortalization. To examine the possible involvement of multiple gene alterations in extended lifespan or immortalization of normal human fibroblasts, normal human fibroblasts (WHE-7 cells) and skin fibroblasts (MDAH 087 cells) derived from a Li-Fraumeni syndrome patient with a mutated p53 allele were periodically irradiated with x rays. All six unirradiated control MDAH 087 cell cultures ceased growing by 37 population doublings (PD) and senesced. In contrast, one of six MDAH 087 cultures irradiated one to three times with x rays (2 or 4 Gy at 2 Gy/min) grew continuously for over 450 PD, indicating that the cells were immortal. All 12 WHE-7 cell cultures that were irradiated under the same conditions and all 20 unirradiated control WHE-7 cultures did not become immortal. Single-stranded DNA conformation analysis and DNA sequencing revealed that no additional mutations were induced by x-ray irradiation in exons 2-10 of the p53 gene of the immortal cells (LCS-4X2 cells) and that loss of the wild-type p53 gene was necessary but not sufficient for immortalization. Karyotypic analysis and chromosome painting analysis demonstrated that a high percentage (more than 98%) of LCS-4X2 cells had lost chromosome 6. Irradiation of WHE-7 cells nine times with x rays (2 Gy at 2 Gy/min) extended the cells' lifespans but did not immortalize them. These cells (X9 cells) exhibited a nonrandom karyotypic alteration, monosomy 6, that was confirmed by loss of heterozygosity for a polymorphic dinucleotide repeat sequence on chromosome 6. DNA analysis showed that X9 cells had no mutations in exons 2-10 of the p53 gene. DNA fingerprint analysis with a multi-locus probe detected DNA rearrangements in LCS-4X2 cells and X9 cells, indicating that both cells could have mutations at a gene or genes other than the p53 gene. The results are consistent with our previous findings that cells with a mutation in one gene involved in cellular senescence (i.e., the p53 gene in Li-Fraumeni fibroblasts) are prone to immortalization. Furthermore, we conclude that immortalization of normal human fibroblasts is a multistep process involving loss or inactivation of multiple genes, such as p53 and a gene on chromosome 6. Loss of a gene on chromosome 6 without p53 alterations extends cellular lifespan without immortalizing the cells.
Mol Carcinog 1997 Jan
PMID:Extended lifespan and immortalization of human fibroblasts induced by X-ray irradiation. 902 8

The Li-Fraumeni syndrome is a rare autosomal-dominant disease whose hallmark is a predisposition to a wide range of cancers among members of a family. Many of these families have a germline mutation within the tumor suppressor gene TP53, which encodes the p53 protein. The inheritance of a mutant TP53 allele results in a 25-fold increase in the chance of developing cancer by 50 years of age, compared with the general population. TP53 mutations are also very common in the development of somatic tumors. This article reviews the biological and biochemical role of p53 in the susceptibility to cancer in Li-Fraumeni syndrome.
Mol Med Today 1997 Sep
PMID:The Li-Fraumeni syndrome: an inherited susceptibility to cancer. 930 89

1. Using simultaneous recordings of the field EPSP and the population spike in the CA1 neurons of guinea pig hippocampal slices, we confirmed that delivery of a high-frequency stimulation (tetanus: 100 pulses at 100 Hz) produced robust long-term potentiation of synaptic efficacy (LTP) in two independent components, a synaptic component that increases field excitatory postsynaptic potentials (EPSPs) and a component that results in a larger population spike amplitude for a given EPSP size (E-S potentiation). 2. In the same cells, reversal of LTP (depotentiation; DP) in the field EPSP and in the E-S component is achieved by delivering low-frequency afferent stimulation (LFS: 1 Hz, 1000 pulses) 20 min after the tetanus. 3. When the tetanus or LFS was applied to CA1 inputs in the presence of an adenosine A1 receptor antagonist, 8-cyclopentyltheophylline (1 microM), the field EPSP was enhances in LTP and attenuated in DP, while the E-S relationship was not significantly affected in either LTP or DP. 4. When similar experiments were performed using an A2 receptor antagonist, CP-66713 (10 microM), the field EPSP was blocked in LTP but facilitated in DP, while E-S potentiation was enhanced during both LTP and DP. 5. The results show that endogenous adenosine, acting via A1 or A2 receptors, modulates both the synaptic and the E-S components of the induction and reversal of LTP. Based on the results, we discuss the key issue of the contribution of these receptors to the dynamics of neuronal plasticity modification in hippocampal CA1 neurons.
Cell Mol Neurobiol 2000 Jun
PMID:Effects of A1 and A2 adenosine receptor antagonists on the induction and reversal of long-term potentiation in guinea pig hippocampal slices of CA1 neurons. 1078 32

Genomic instability is often caused by mutations in genes that are involved in DNA repair and/or cell cycle checkpoints, and it plays an important role in tumorigenesis. Poly(ADP-ribose) polymerase (PARP) is a DNA strand break-sensing molecule that is involved in the response to DNA damage and the maintenance of telomere function and genomic stability. We report here that, compared to single-mutant cells, PARP and p53 double-mutant cells exhibit many severe chromosome aberrations, including a high degree of aneuploidy, fragmentations, and end-to-end fusions, which may be attributable to telomere dysfunction. While PARP(-/-) cells showed telomere shortening and p53(-/-) cells showed normal telomere length, inactivation of PARP in p53(-/-) cells surprisingly resulted in very long and heterogeneous telomeres, suggesting a functional interplay between PARP and p53 at the telomeres. Strikingly, PARP deficiency widens the tumor spectrum in mice deficient in p53, resulting in a high frequency of carcinomas in the mammary gland, lung, prostate, and skin, as well as brain tumors, reminiscent of Li-Fraumeni syndrome in humans. The enhanced tumorigenesis is likely to be caused by PARP deficiency, which facilitates the loss of function of tumor suppressor genes as demonstrated by a high rate of loss of heterozygosity at the p53 locus in these tumors. These results indicate that PARP and p53 interact to maintain genome integrity and identify PARP as a cofactor for suppressing tumorigenesis.
Mol Cell Biol 2001 Jun
PMID:DNA strand break-sensing molecule poly(ADP-Ribose) polymerase cooperates with p53 in telomere function, chromosome stability, and tumor suppression. 1135 11


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