Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in the p53 gene are frequently observed in a wide variety of human cancers. To elucidate the role of p53 in tumorigenesis of the dog, we analyzed nine mammary tumor cell lines, and the primary or metastatic tumors used for their establishment, for the presence of genomic p53 abnormalities. Possible genomic rearrangements were analyzed by Southern blotting using a canine cDNA probe. More subtle alterations were identified by single strand conformation polymorphism (SSCP) analysis for which we partially characterized the canine p53 gene (codon 109-388 as compared to the human gene). The presence of mutations in SSCP fragments with altered mobility was confirmed by DNA sequencing. Three of the nine cell lines showed a mutated p53 gene. All were missense mutations accompanied by loss of the wild type allele. The point mutations, at codon 176 (TGC * TTC), 236 (TAC * AAC) and 245 (GGC * GCC), were all located in one of the four regions that are frequently affected in human cancers. Analysis of the DNA extracted from the tumors of origin demonstrated the presence of two of these point mutations. These findings indicate the involvement of the p53 gene in the genesis of canine tumors in a way comparable to that of human tumors.
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PMID:P53 mutations in mammary tumor cell lines and corresponding tumor tissues in the dog. 904 50

Thirty percent of human breast cancers have amplification of ERBB2, often in conjunction with mutations in p53. The most common p53 mutation in human breast cancers is an Arg-to-His mutation at codon 175, an allele that functions in a dominant oncogenic manner in tumorigenesis assays and is thus distinct from loss of p53. Transgenic mice expressing mouse mammary tumor virus-driven neu transgene (MMTV-neu) develop clonal mammary tumors with a latency of 234 days, suggesting that other events are necessary for tumor development. We have examined the role of mutations in p53 in tumor development in these mice. We have found that 37% of tumors arising in these mice have a missense mutations in p53. We have directly tested for cooperativity between neu and mutant p53 in mammary tumorigenesis by creating bitransgenic mice carrying MMTV-neu and 172Arg-to-His p53 mutant (p53-172H). In these bitransgenic mice, tumor latency is shortened to 154 days, indicating strong cooperativity. None of the nontransgenic mice or the p53-172H transgenic mice developed tumors within this time period. Tumors arising in the p53-172H/neu bitransgenic mice were anaplastic and aneuploid and exhibited increased apoptosis, in distinction to tumors arising in p53-null mice, in which apoptosis is diminished. Further experiments address potential mechanisms of cooperativity between the two transgenes. In these bitransgenic mice, we have recapitulated two common genetic lesions that occur in human breast cancer and have shown that p53 mutation is an important cooperating event in neu-mediated oncogenesis.
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PMID:neu/ERBB2 cooperates with p53-172H during mammary tumorigenesis in transgenic mice. 915 14

The human hepatitis B virus (HBV) protein pX is a multifunctional regulatory protein that is known to affect both transcription and cell growth. Here we describe induction of apoptosis in NIH 3T3 polyclonal cell lines upon stimulation of pX expression from a dexamethasone inducible mouse mammary tumor virus (MMTV)-X expression vector. The effect of long-term pX expression on the cell survival of mouse fibroblasts was confirmed in colony generation assays. This effect is not shared either by the other HBV products and it is c-myc mediated, as shown by the use of a dominant negative deletion mutant of c-myc. pX also sensitize cells to programmed cell death after exposure to DNA damaging agents. Taking advantage of stable transfectants carrying the p53val135 temperature-sensitive allele, we directly demonstrate that induction of apoptosis by pX requires p53. In p53 null mouse embryo fibroblasts pX activates transcription and confers an evident growth advantage without loss of cell viability. Although pX protein was not detectable in the experimental conditions we used, our results indicate that its expression affects both cell growth and cell death control.
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PMID:The hepatitis B virus X gene induces p53-mediated programmed cell death. 922 32

Loss or mutation of p53 may have multiple biological and genetic effects that result in accelerated tumor progression. Loss of p53 in some tumors has been correlated with a marked decrease in tumor cell apoptosis. p53 loss may also accelerate tumor growth through an increase in cell proliferation rates. To examine the effects of p53 loss on tumor progression in a controlled experimental context, we previously crossed p53-deficient mice to mammary tumor-susceptible Wnt-1 transgenic (TG) mice. The resulting female Wnt-1 TG offspring of this cross all developed mammary tumors, regardless of p53 status (p53+/+, p53+/-, or p53-/-). However, female p53-/- Wnt-1 TG mice developed tumors much sooner than their p53+/+ counterparts. In this report, we demonstrate that the average growth rates of tumors missing (p53-/-) or losing p53 (p53+/- with loss of heterozygosity) are accelerated compared to tumors with both wild-type p53 alleles (p53+/+). This accelerated growth rate appears to be due primarily to increases in rates of tumor cell proliferation. Tumor cell apoptotic levels were modest and were not measurably different in the presence or absence of wild-type p53. These results differ substantially from other mouse tumor models in which p53 loss was closely correlated with accelerated growth rates through attenuated apoptosis. Thus, the mechanisms by which p53 loss influences tumor progression may differ, depending on the tissue type and/or the oncogenic pathways involved.
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PMID:Absence of p53 in a mouse mammary tumor model promotes tumor cell proliferation without affecting apoptosis. 926 92

Transgenic mice expressing the simian virus 40 large T-antigen (TAG) under the regulatory control of the rat prostatic steroid binding protein C3(1) gene develop mammary carcinomas (in females) and prostate carcinomas (in males). The development of carcinomas occurs several months after the appearance of dysplastic lesions, suggesting that TAG is necessary but insufficient for tumor formation and that other genetic events are involved in this process. TAG is known to bind to p53 and to result in its functional inactivation, which is believed to be a critical step in TAG-induced transformation. We investigated whether the TAG-p53 interaction is rate limiting in the development of phenotypic changes in these transgenic mice by crossing C3(1)/TAG transgenics with mice carrying null mutations of the p53 gene. TAG-expressing animals with a p53+/- genotype developed much more aggressive mammary tumors, as evidenced by increased numbers and size of metastases, than did TAG-expressing animals carrying two wild-type p53 alleles. While p53 was expressed in primary tumors, p53 expression appeared to be reduced or lost in many metastases in mice carrying either the p53+/+ or p53+/- genotypes. The tumorigenic process did not appear to be due to the loss of the second wild-type p53 allele or the gain of dominant oncogenic mutations in p53, as no mutations were detected in either primary or metastatic tumors by polymerase chain reaction--single-strand conformation polymorphism analyses. These findings suggest that despite the presence of TAG, p53 levels influence the characteristics of the late stages of mammary tumor growth and accelerate metastases. Functional loss of p53 and not p53 mutations participates in TAG-induced mammary carcinoma development and progression.
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PMID:Reduced p53 dosage associated with mammary tumor metastases in C3(1)/TAG transgenic mice. 936 6

The farnesyltransferase inhibitor L-744,832 selectively blocks the transformed phenotype of cultured cells expressing a mutated H-ras gene and induces dramatic regression of mammary and salivary carcinomas in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice. To better understand how the farnesyltransferase inhibitors might be used in the treatment of human tumors, we have further explored the mechanisms by which L-744,832 induces tumor regression in a variety of transgenic mouse tumor models. We assessed whether L-744,832 induces apoptosis or alterations in cell cycle distribution and found that the tumor regression in MMTV-v-Ha-ras mice could be attributed entirely to elevation of apoptosis levels. In contrast, treatment with doxorubicin, which induces apoptosis in many tumor types, had a minimal effect on apoptosis in these tumors and resulted in a less dramatic tumor response. To determine whether functional p53 is required for L-744,832-induced apoptosis and the resultant tumor regression, MMTV-v-Ha-ras mice were interbred with p53(-/-) mice. Tumors in ras/p53(-/-) mice treated with L-744,832 regressed as efficiently as MMTV-v-Ha-ras tumors, although this response was found to be mediated by both the induction of apoptosis and an increase in G1 with a corresponding decrease in the S-phase fraction. MMTV-v-Ha-ras mice were also interbred with MMTV-c-myc mice to determine whether ras/myc tumors, which possess high levels of spontaneous apoptosis, have the potential to regress through a further increase in apoptosis levels. The ras/myc tumors were found to respond nearly as efficiently to L-744,832 treatment as the MMTV-v-Ha-ras tumors, although no induction of apoptosis was observed. Rather, the tumor regression in the ras/myc mice was found to be mediated by a large reduction in the S-phase fraction. In contrast, treatment of transgenic mice harboring an activated MMTV-c-neu gene did not result in tumor regression. These results demonstrate that a farnesyltransferase inhibitor can induce regression of v-Ha-ras-bearing tumors by multiple mechanisms, including the activation of a suppressed apoptotic pathway, which is largely p53 independent, or by cell cycle alterations, depending upon the presence of various other oncogenic genetic alterations.
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PMID:A farnesyltransferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis. 941 56

We have generated a transgenic mouse model in which female mice develop ductal mammary adenocarcinomas and male mice develop prostatic adenocarcinomas by using a transgene containing the hormone-responsive rat prostatic steroid binding protein 5' flanking region C3(1) fused to the simian virus 40 (SV40) large T antigen. We have identified some genetic alterations during mammary and prostate tumor progression: (i) p53 is functionally inactivated during mammary cancer development without p53 mutations; (ii) Alterations in apoptosis during mammary tumor progression are p53 and bcl-2 independent; (iii) Ha-ras mutations occur early in the development of prostate cancer. This unique animal model offers the opportunity to study multistep tumorigenesis in these organs.
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PMID:Genetic alterations in the development of mammary and prostate cancer in the C3(1)/Tag transgenic mouse model. 945 74

Intact female Beagles from life-span studies in the Lovelace Respiratory Research Institute colony were examined for mammary tumor incidence. The breeding colony, founded in 1963, produced five generations from 28 founder females. After proportional hazards analysis, two maternal families were shown to have markedly different phenotypes, one susceptible and one resistant to mammary neoplasia, as compared with the entire colony. When tumors were subdivided into benign and malignant based on local invasiveness, familial differences in tumor incidence were preserved for each tumor type. Fifty-seven females in the susceptible family developed 149 benign and 39 malignant tumors, and 95 females in the resistant family developed 70 benign and 20 malignant tumors. The ratio of benign to malignant tumors of about 4:1 for both families was higher than expected. Using Kaplan-Meier and log-rank analyses, the susceptible family had a 50% malignant tumor incidence by age 13.6 years, whereas the resistant family did not have a 50% incidence until 17.0 years (P = 0.0065). Because of marked censoring, Kaplan-Meier analyses could not provide an estimate of the 50% benign tumor incidence; mean incidence age was calculated instead. These estimates for benign tumors for susceptible and resistant families were 10.8 and 13.8 years (P = 0.0001), respectively. Using chi(2) tests, families had no differences in the occurrence of the types of benign (P = 0.098) or malignant (P = 0.194) tumors or in the ratio of benign to malignant tumors (P = 0.778). Immunohistochemical analysis of malignant tumors from both families did not demonstrate differences in p53 mutation rate or p185erbB-2 expression. These results suggest that 1) genetic factors produce familial differences in the age of onset of both benign and malignant mammary tumors; histologic types do not segregate by family; 2) the ratio of benign to malignant tumors is greater than formerly reported; and 3) neither p53 nor p185erbB-2 alterations are the basis for the familial predisposition.
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PMID:A canine model of familial mammary gland neoplasia. 959 80

Scatter factor (SF) (hepatocyte growth factor) is a cytokine that may play a role in human breast cancer invasiveness and angiogenesis. We now report that SF can block the induction of apoptosis by various DNA damaging-agents, including cytotoxic agents used in breast cancer therapy. SF protected MDA-MB-453 human breast cancer cells, EMT6 mouse mammary tumor cells and MDCK renal epithelial cells against apoptosis induced by adriamycin (ADR), X-rays, ultraviolet radiation, and other agents. Protection was observed in assays of DNA fragmentation, cell viability (MTT), and clonogenic survival. Protection of MDA-MB-453 cells against ADR was dose- and time-dependent; maximal protection required pre-incubation with 75-100 ng/ml of SF for 48 h or more. Protection required functional SF receptor (c-Met), but was not dependent on p53. Western blotting analysis revealed that pre-treatment of MDA-MB-453 cells with SF inhibited the ADR-induced decreases in the levels of Bcl-XL, an anti-apoptotic protein related to Bcl-2; and the dose-response and time course characteristics for SF-mediated increases in the Bcl-XL protein levels of ADR-treated cells were consistent with the degrees of protection against apoptosis observed under the same conditions. Furthermore, Bcl-XL levels were not down-regulated by ADR in MDA-MB-231 breast cancer cells, consistent with the finding that SF failed to protect these cells against ADR, despite the fact that they contain functional c-Met receptor. In contrast to Bcl-XL, SF blocked ADR-induced increases in c-Myc and inhibited the expression of p21WAF1/CIP1 and of the BRCA1 protein in MDA-MB-453 cells. However, SF did not cause significant changes in the cell cycle distribution of ADR-treated cells. These findings suggest that SF-mediated protection of human breast cancer cells may involve inhibition of one or more pathways required for the activation of apoptosis and may particularly target the anti-apoptotic mitochondrial membrane pore-forming protein Bcl-XL as a component of the protective mechanism. By implication, the accumulation of SF within human breast cancers may contribute to the development of a radio- or chemoresistant phenotype.
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PMID:Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA-damaging agents. 967 97

To determine whether canine malignancies share common genetic lesions with their human counterparts, and are thus potentially interesting model systems in which to pose questions regarding tumor etiology and progression, we have elucidated the entire exon/intron structure of the canine p53 gene. A search for p53 gene abnormalities in mammary tumor tissue was undertaken utilizing single strand conformation polymorphism analysis. Mutations were detected in exons 4, 5, 6, and 7 of the p53 gene and consisted of nonsense, splicing, and frameshift mutations. None of 11 benign tumors and 6 of 40 primary carcinomas (15%) were found to harbor subtle p53 mutations. In 14 carcinomas examined the results in primary tumors and metastases were the same. These findings implicate involvement of this gene in the genesis of some malignant canine tumors, in a fashion similar to their human counterparts.
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PMID:Genomic organization of the canine p53 gene and its mutational status in canine mammary neoplasia. 980 16


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