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)

Cancer chemoprevention uses natural- or synthetic chemical compounds to reverse, suppress or to prevent one or more of the biological events leading to the development of cancer. Chemopreventive agents are classified as blocking or suppressing according to their action on either the initiation or promotion-progression phases in experimental models using carcinogen treated animals. Transgenic animal technology has resulted in a plethora of murine models for cancer research providing insight into the complex oncogenic events contributing to the loss of cell cycle control and tumourigenesis. Transgenic models also offer an important opportunity to identify and study both tumourigens and chemopreventive agents. However, so far chemoprevention has in such models only been investigated to a limited degree and primarily in models with inactivated tumour suppressor genes. Studies show that spontaneous tumour developing due to loss of p53 function may be offset by preventive measures. The preventive actions of retinoids and polyamine synthesis inhibitors have been studied in the PIM mouse susceptible to lymphoma development. Most chemopreventive studies have been performed on murine familial adenomatous polyposis (FAP) models, which carry one non-functional apc gene and develop multiple intestinal adenomas upon inactivation of the wild type allele. Particularly non-steroidal anti-inflammatory drugs NSAIDs, which block COX-2, but also food components such as n-3 fatty acids show promising chemopreventive effects in these models. Transgenic cancer models demonstrate a strong gene-environment interaction, which is promising for the development of chemopreventive strategies.
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PMID:Use of transgenic mice in identifying chemopreventive agents. 1072 Jul 73

We herein summarize the reports on genetic changes in precancerous lesions in the gastrointestinal tract. It has been reported that with esophageal lesions such as dysplasia and Barrett's esophagus there is a high frequency of p53 mutations. Among gastric lesions, some cases of chronic atrophic gastritis have been shown to harbor K-ras mutations. p53 and APC mutations in intestinal metaplasia have also been demonstrated, as have APC mutations in flat adenomas. With colorectal lesions, it has been reported that K-ras, DCC, p53 mutations commonly occur while APC mutations are also seen in cases of adenoma-carcinoma. p53 and K-ras mutations have been demonstrated with serrated adenoma, and K-ras mutations with hyperplastic polyps APC mutations in familial polyposis coli, LKB1 mutations in Peutz-Jeghers syndrome, and SMAD4/DPC4 mutations in juvenile polyposis syndrome have been found. Besides these genes, other genetic changes likely occur in carcinogenesis among those with hereditary diseases. K-ras mutations in aberrant crypt foci and hMSH2 mutations in ulcerative colitis have been found. Research into the genetic changes associated with cancerous lesions should lead to the development of early diagnosis and treatment methods for gastrointestinal cancer as well as the improved comprehension of carcinogenesis.
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PMID:[Genome analyses for precancerous lesions in the gastrointestinal tract]. 1074 Jun 25

We described two patients (brother and sister) with familial adenomatous polyposis of the colon. It is an inherited disease with autosomal dominant pattern of inheritance. The incidence is 1:8.000, with usual onset of polyps development late in the first decade of life or during adolescence, and malignant alteration up to the fourth decade of life. APC gene located on long arm of chromosome 5 is responsible for occurrence of the disease that presents with onset of multiple adenomatous polyps in the colon (from some of them to 1000). The treatment includes chemoprevention by sulindac or aspirin that prevents or reverse process of carcinogenesis. Surgical approach is preventive colectomy up to 20 (25) years of life. APC gene mutation (deletion at codon 1309-1311) was proven by DNA analysis from blood and polyp in both patients. There was no evidence of mutations of genes p53 and K-ras. Preventive colectomy is planned as soon as possible.
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PMID:[Familial adenomatous colonic polyposis]. 1104 May 35

This review focuses on the functional role and structural features of the genes involved in common hereditary cancers. Most of these tumors are sporadic and the genetic alterations responsible for their genesis take place over several cell generations; nevertheless, 5 to 10% of the human tumors are hereditary, with a rapid development. Cancer susceptibility genes have been classified as "gatekeepers" (e.g. RB1, ki-ras) and "caretakers" (e.g. hMLH1 and hMSH2, BRCA1). The first step in identifying individuals at high risk of developing a specific inherited form of cancer, and who should therefore undergo genetic tests, is the detailed construction of family history (an accurate cancer family history that includes at least three generation pedigrees, an appropriate cancer risk assessment and an effective genetic counseling). At present, the most useful methods of risk assessment are those performed on the following genes: BRCA1 and BRCA2 especially for hereditary breast and ovarian cancer, hMLH1 and hMSH2 for hereditary non polyposis colorectal cancer, APC for familial adenomatous polyposis, ret for medullary thyroid carcinoma, p53 for the Li-Fraumeni syndrome, p16 for melanoma and RB1 for retinoblastoma. In conclusion, the development of new diagnostic tests will permit a more accurate assessment of risk in individuals who have not so far shown any sign or symptom of the disease.
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PMID:Hereditary common cancers: molecular and clinical genetics. 1120 30

Germline mutation in the APC gene is required for the initiation of the development of familial adenomatous polyposis (FAP). According to Fearon and Vogelstein model, further somatic mutations in the K-ras oncogene, DCC gene and p53 tumor suppressor gene are prerequisite for development of colon carcinoma. We have found that the germline mutations in the DNA isolated from lymphocytes of an 18 years old girl with extraordinary expressive phenotype in codons 1060-1061 of the APC gene result in truncation of the APC protein. The mutation in codons 12 and 13 of the K-ras oncogene was not detected, but another germline mutation was found in codon 210 of the p53 gene. Furthermore, no one of these germline mutations was detected in the DNA of peripheral blood lymphocytes of the patient's 21 years old healthy sister. Until now, there has been no evidence about the expressive phenotype due to mutation in codons 1060-1061 of the APC gene; the role of germline missense mutation in codon 210 of the p53 gene in the FAP malignant process remains to be elucidated too. The effect of the combination of germline mutation in two different tumor suppressor genes in the progress of disease is discussed.
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PMID:A double germline mutations in the APC and p53 genes. 1126 56

Chronic obstructive uropathy (COU) created by unilateral ureteric ligation is associated with increased renal cell apoptosis and p53 expression. Genetically engineered mice were used to examine the role of p53 in renal cell apoptosis in COU and the involved molecular pathways. Obstructed kidneys in p53+/+, p53+/-, and p53-/- mice were examined at days 4, 7, 15, 20, and 30 for apoptosis, and mRNA were examined for p53, members of the bcl-2 family, the death receptor family, and the common effectors of apoptosis. Obstructed kidneys in p53+/- and p53-/- mice exhibited equal attenuation of tubular and interstitial cell apoptosis (70 and 50%, respectively), compared with p53+/+ mice. However, p53 gene deficiency did not confer complete protection from apoptosis. Obstructed kidneys from p53-/- mice did not express p53 mRNA, whereas those from p53+/- and p53+/+ mice displayed mild and marked increase in their expression, respectively. Obstructed kidneys in p53+/+, p53+/-, and p53-/- mice displayed upregulation of mRNA for members of the bcl-2 family and most of the death receptor family, except for a lower level of tumor necrosis factor receptor-1, TRAIL, and FAP in p53+/+ mice. Obstructed kidneys in p53-/- and p53+/- mice showed virtual absence of caspase 11 and marked attenuation of caspases 1 and 12, contrasted with their strong expression in p53+/+ kidneys. These data suggest that apoptosis in obstructed kidneys involves p53-dependent as well as p53-independent pathways. The p53-dependent pathway may involve activation of caspases 1, 11, and 12, whereas the p53-independent pathway may involve activation of members of the bcl-2 and death receptor families.
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PMID:Role of p53-dependent activation of caspases in chronic obstructive uropathy: evidence from p53 null mutant mice. 1131 57

Pancreatoblastomas are unusual malignant neoplasms of the pediatric pancreas that may also rarely affect adults. The molecular pathogenesis of pancreatoblastomas is unknown. They are clinicopathologically distinct from adult pancreatic ductal adenocarcinomas, but their occasional occurrence in patients with Beckwith-Wiedemann syndrome and the case presented here of a pancreatoblastoma in an adult patient with familial adenomatous polyposis (FAP) suggests that they might bear a genetic similarity to other infantile embryonal tumors such as hepatoblastomas. We analyzed a series of nine pancreatoblastomas for mutations common to other embryonal malignancies including somatic alterations in the adenomatous polyposis coli (APC)/beta-catenin pathway and chromosome 11p, using immunohistochemistry for beta-catenin, 5q and 11p allelic loss assays, and direct DNA sequencing of exon 3 of the beta-catenin gene and the mutation cluster region of the APC gene. In addition, we analyzed the pancreatoblastomas for alterations found in adult-type pancreatic ductal adenocarcinomas including mutations in the K-ras oncogene and the p53 and DPC4 tumor suppressor genes, using direct DNA sequencing of exon 1 of K-ras and immunohistochemistry for p53 and Dpc4. Allelic loss on chromosome 11p was the most common genetic alteration in pancreatoblastomas, present in 86% (six of seven informative cases). Molecular alterations in the APC/beta-catenin pathway were detected in 67% (six of nine), including five neoplasms with activating mutations of the beta-catenin oncogene and the one FAP-associated tumor with biallelic APC inactivation (germline truncating mutation combined with loss of the wild-type allele); seven neoplasms showed abnormal nuclear accumulation of beta-catenin protein. In contrast, loss of Dpc4 protein expression was present in only two cases (one diffuse and one focal), and no alterations in the K-ras gene or p53 expression were detected. Our findings indicate that pancreatoblastomas are genetically distinct from the more common pancreatic ductal adenocarcinomas, but bear a close molecular pathogenesis to hepatoblastomas. In addition, pancreatoblastoma may represent an extracolonic manifestation of FAP.
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PMID:Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas : frequent alterations in the APC/beta-catenin pathway and chromosome 11p. 1194 38

N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatments for a long period induced morphological and molecular alterations in the benign human colorectal polyps which were maintained in the severe combined immunodeficient C.B17/N-scid/scid mice. Thirty four xenografts of colorectal polyps from five solitary polyp and three familial polyposis patients were examined for K-ras and p53 mutations. Six K-ras mutations were induced in 16 grafts treated with MNNG more than five times, while no K-ras mutations were detected in 14 untreated grafts (P<0.05). Additional and new K-ras mutations were also induced in two polyps in which K-ras mutation had pre-existed. p53 mutations were not observed in both MNNG-treated and untreated groups. The mutations in K-ras gene were induced at codon 12 (GGT-->GAT) except one at codon 13 (GGC-->GGT). The results indicate that K-ras mutation plays an important role in human colorectal carcinogenesis as is the case in experimental animals.
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PMID:Effects of N-methyl-N'-nitro-N-nitrosoguanidine on the human colorectal polyps consecutively maintained in SCID mice. 1204 57

Reports on the association of papillary thyroid carcinoma with paraganglionic or desmoid tumors have appeared infrequently. The former setting usually affects middle-aged females; the latter is typical of familial adenomatous polyposis. We report the case of a 69-yr-old man in whom two abdominal masses had been instrumentally detected following an access of abdominal pain. Save for a moderate hypertension, he was asymptomatic and an impalpable thyroid nodule was detected by ultrasonography. A high urinary noradrenaline output and cytology of the masses raised the suspicion of pheochromocytoma. At laparotomy, an adrenal pheochromocytoma and a paracaval paraganglioma were excised. Subsequently, hemithyroidectomy was performed, and histopathology revealed papillary microcarcinoma. A nodule of desmoid tumor was also removed from the abdominal wall. An analysis of RET, APC, and TP53 gene mutations, and of RET and NTRK1 gene rearrangements, yielded negative results. No in vitro transforming activity was detected in the tumor DNA when assayed in transfection experiments. The lack of a consistent family history also made unlikely the possibility of identifying the putative germline defect by linkage analyses. Should this unusual aggregation of tumors represent a new entity, a number of genetic alterations have now been excluded.
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PMID:Concurrent Pheochromocytoma, Paraganglioma, Papillary Thyroid Carcinoma, and Desmoid Tumor: A Case Report with Analyses at the Molecular Level. 1211 65

Identification of the adenoma-carcinoma sequence with its corresponding molecular genetic alterations has significantly increased our understanding of the pathogenesis of colorectal carcinoma (CRC). This route of carcinogenesis, hallmarked by genetic instability at the chromosomal level, is conventionally called the "suppressor pathway" because it is frequently accompanied by biallelic loss or inactivation of specific tumor suppressor genes (APC, p53 etc.). However, not all genetic alterations involved in carcinogenesis in the colon fit into this linear tumor progression model. In part, hereditary and sporadic CRC develops from a genetic instability at the DNA level (detected as microsatellite instability, MSI). This route of carcinogenesis in the colon is also termed the "mutator pathway". While familial adenomatous polyposis (FAP) is grouped into the "suppressor pathway" category, hereditary nonpolyposis colorectal cancer (HNPCC) typically follows the "mutator pathway". Whereas most MSI cancers presumably develop from colorectal adenomas, emerging evidence indicates that some MSI tumors may develop from certain hyperplastic polyps via a "serrated adenoma" (termed the "serrated pathway"). This review shall present the different ways that colon cancer can develop and illustrate the molecular alterations and morphological and clinical correlates that characterize these carcinogenesis pathways. The review shall conclude with a discussion of aspects relevant to clinical practice.
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PMID:[Pathogenesis of colorectal carcinoma]. 1239 9


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