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)

Many human tumors harbor mutations that result in deregulation of Cdk4 activity. Most of these mutations involve overexpression of D-type cyclins and inactivation of INK4 inhibitors. In addition, a mutation in the Cdk4 protein has been described in patients with familial melanoma (Wolfel, T., Hauer, M., Schneider, J., Serrano, M., Wolfel, C., et al. (1995) Science 269, 1281-1284; Zuo, L., Weger, J., Yang, Q., Goldstein, A. M., Tucker, M. A., et al. (1996) Nat. Genet. 12, 97-99). This mutation, R24C, renders the Cdk4 protein insensitive to inhibition by INK4 proteins including p16(INK4a), a major candidate for the melanoma susceptibility locus. Here we show that knock-in mice expressing a Cdk4 R24C allele are highly susceptible to melanoma development after specific carcinogenic treatments. These tumors do not have mutations in the p19(ARF)/p53 pathway, suggesting a specific involvement of the p16(INK4a)/Cdk4/Rb pathway in melanoma development. Moreover, by using targeted mice deficient for other INK4 inhibitors, we show that deletion of p18(INK4c) but not of p15(INK4b) confers proliferative advantage to melanocytic tumor growth. These results provide an experimental scenario to study the role of Cdk4 regulation in melanoma and to develop novel therapeutic approaches to control melanoma progression.
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PMID:Invasive melanoma in Cdk4-targeted mice. 1160 89

Several molecular and genetic changes have been found in pituitary adenomas. We looked for correlations between these changes and the degree of invasiveness of the tumors. The invasiveness of 11 pituitary adenomas was graded by Hardy classification. We examined the retinoblastoma gene (RB1.20 on chromosome 13q) and the region around the MEN1 locus (chromosome 11q13.1-5) for loss of heterozygosity. Also examined are p53 mutations using single strain conformation polymorphism, p53 protein overexpression using immuno cytochemistry, homozygous deletions of p15 and p16 by polymerase chain reaction, and cellular proliferative activity using MIB-1 antibody. Six tumors (54.5%) had an LOH at either RB1.20 or the MEN1 locus. LOHs were found more frequently in Grade 4 and stage E tumors (72% and 67%) than in Grade 3 and stage D tumors (25% and 40%). However, no mutation or overexpression of p53 was found. No homozygous deletions of p15 or p16 were identified. The cell proliferative index ranged from 0 to 3%. LOH at 11q13 and 13q may be valuable in predicting the invasiveness of pituitary adenomas.
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PMID:Clinical significance of molecular genetic changes in sporadic invasive pituitary adenomas. 1164 45

Natural killer (NK) cell neoplasms, which are derived from mature or precursor NK cells, are rare diseases and are observed predominantly in Asian countries. We analyzed the status of the Rb, p53, p15INK4B, p16INK4A and p14ARF genes in these diseases by Southern blot, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and western blot analysis. We used 31 NK cell neoplasms, including four cell lines derived from NK cell neoplasms, 3 myeloid / NK cell precursor acute leukemias, 4 blastic NK cell lymphoma / leukemias, 4 aggressive NK cell leukemia / lymphomas, 4 nasal NK cell lymphomas, and 12 chronic NK lymphocytosis. We found gene amplification of the p53 gene in one nasal NK cell lymphoma, and point mutations of the p53 gene in one blastic NK cell lymphoma / leukemia and one chronic NK lymphocytosis. In addition, homozygous deletions of p15, p16 and p14 genes in 5 out of 31 samples were detected; 3 were from nasal NK cell lymphoma and 2 from blastic NK cell lymphoma / leukemia. Also hemizygous deletion of the Rb gene in one blastic NK cell lymphoma was detected. Rb proteins were highly expressed in one cell line as well as two myeloid / NK cell precursor acute leukemias. In other cell lines, complete loss and an aberrant migration pattern of Rb protein expression were observed. Comparative genomic hybridization suggested that the homozygous deletions of the p15, p16 and p14 were subtle chromosomal deletions and could not be identified by standard karyotyping in some cases. Although the number of cases we analyzed was not large, alterations identified in the Rb, p53, p16, p15 and p14 genes are of significance and might be associated with tumorigenesis in NK cell neoplasms.
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PMID:Molecular analysis of tumor suppressor genes, Rb, p53, p16INK4A, p15INK4B and p14ARF in natural killer cell neoplasms. 1167 55

The majority of clonal hematologic syndromes, including lymphoproliferative, myeloproliferative, and myelodysplastic disorders, tend to undergo transformation. However, the frequency of transformation varies widely. For example, transformation is almost invariable in chronic myelogenous leukemia, but it is infrequent in other myeloproliferative disorders. Similarly, transformation occurs in approximately 33% of follicular lymphomas but less commonly in other lower-grade lymphomas. At a genetic level, although some secondary lesions are seen across the spectrum of transformation syndromes (such as loss of function of p53 and p15/p16), there is considerable intra- and interdisease variability, with no common denominator. This review of the literature will discuss these transformations, noting their frequency, pathologic changes observed, clinical syndromes described, underlying genetic correlates, and prognostic and therapeutic implications.
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PMID:Clinical syndromes of transformation in clonal hematologic disorders. 1169 May 75

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma, a cancer of which the incidence has been increasing at an alarming rate in Western countries. p16(INK4a) lesions occur frequently in esophageal adenocarcinomas but their role in neoplastic progression is not well understood. We detected 9p21 loss of heterozygosity, p16 CpG island methylation, and p16 mutations in biopsies from 57%, 61%, and 15%, respectively, of 107 patients with BE. In contrast, no mutations were found in p14(ARF) or p15, and methylation was found in only 4% and 13%, respectively. >85% of Barrett's segments had clones with one (p16+/-) or two (p16-/-) p16 lesions. Both p16+/- and p16-/- clones underwent extensive expansion involving up to 17 cm of esophageal mucosa. The prevalence of established biomarkers in BE, such as 17p (p53) loss of heterozygosity, aneuploidy, and/or increased 4N (tetraploid) populations, increased from 0% to 20% to 44% in patients whose biopsies were p16+/+, p16+/-, and p16-/-, respectively (P < 0.001). Barrett's segment lengths also increased with change in p16 status with a median of 1.5, 6.0, and 8.0 cm for patients with p16+/+, p16+/-, and p16-/- biopsies, respectively (P < 0.001). We conclude that most Barrett's metaplasia contains genetic and/or epigenetic p16 lesions and has the ability to undergo clonal expansion, creating a field in which other abnormalities can arise that can lead to esophageal adenocarcinoma.
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PMID:p16(INK4a) lesions are common, early abnormalities that undergo clonal expansion in Barrett's metaplastic epithelium. 1171 61

Cellular senescence has been proposed to be an in vitro and in vivo block that cells must overcome in order to immortalize and become tumorigenic. To characterize these pathways, we focused on changes in the cyclin-dependent kinase inhibitors and their binding partners that underlie the cell cycle arrest at senescence. As a model, we utilized normal human prostate epithelial cell (HPEC) and human uroepithelial cell (HUC) cultures. After 30-40 population doublings cells became growth-arrested in G0/1 with a threefold decrease in Cdk2-associated activity, a point defined as pre-senescence. Temporally following this growth arrest, the cells develop a senescence morphology and express senescence-associated beta-galactosidase (SA-beta-gal). Levels of p16(INK4a) and p57(KIP2) rise in HUCs during progressive passages, whereas only p16 increases in HPEC cultures. The induced expression of p57, similar to p16, produces a senescent-like phenotype. pRB, cyclin D, p19(INK4d) and p27(KIP1) decrease in both cell types. We find that p53, p21(CIP1) and p15(INK4b) are transiently elevated in HPECs and HUCs at the pre-senescent growth arrest, then return to low proliferating levels at terminal senescence. Analysis of p53, p21(CIP1), p15(INK4b), p16(INK4a), and p57(KIP2) reveals altered expression in immortalized, non-tumorigenic HPV16 E6 and E7 prostate lines and in tumorigenic prostate cancer cells. These results indicate: (i) the existence of a subset of growth inhibiting genes elevated at the onset of the senescence, (ii) a distinct class of genes involved in the maintenance of senescence, and (iii) the frequent inactivation of these pathways during immortalization.
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PMID:Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. 1178 34

Recently, a series of shared molecular pathways have emerged that have in common a significant role in the pathogenesis and progression of both atherosclerosis and cancer. Oxidative stress and the cellular damage that results from it have been implicated in a wide variety of disease processes including atherogenesis and neoplasia. Toxic metabolites produced by cigarette smoking and increased dietary fat intake are implicated in the pathogenesis of both diseases. It has been hypothesized that atherosclerosis may begin when an injury or infection mutates or transforms a single arterial smooth muscle cell in the progenitor of a proliferative clone similar to the most widely held theory of carcinogenesis. Cell proliferation regulatory pathways including genes involved in the GIS checkpoint (p53, pRb, p15, p16, and cyclins A, D, E, and cdk 2,4) have been associated with plaque progression, stenosis and restenosis after angioplasty as well as in cancer progression. Alterations in cell adhesion molecules (integrins, cadherin-catenins) have been linked to plaque formation and thrombosis as well as to tumor invasion and metastasis. Altered expression of proteases associated with thrombolysis has been implicated in atherosclerotic plaque expansion and hemorrhage and in the invasion and metastasis of malignancy. Ligand-growth factor receptor interactions (tyrosine kinases) have been associated with early atherosclerotic lesions as well as cancer development and spread. Nuclear transcription factors such as NFkappaB have been associated with progression of both diseases. Angiogenesis modulators have recently been linked to plaque expansion and restenosis of atherosclerotic lesions as well as local and metastatic tumor expansion. Common disease treatments, such as the use of growth factor inhibitors and radiation treatment, established anticancer treatments, were recently introduced into atherosclerosis therapeutic strategies to prevent restenosis after angioplasty and endarterectomy. In conclusion, a series of molecular pathways of disease development and progression common to atherosclerosis and cancer support that the world's two most common diseases are far more closely aligned than previously believed and that emerging anti-inflammatory and antiproliferative therapeutic strategies may ultimately be efficacious in both conditions.
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PMID:Atherosclerosis and cancer: common molecular pathways of disease development and progression. 1179 76

Treatment with thyroid hormone (TH) results in shrinkage of a thyrotropic tumor grown in a hypothyroid host. We used microarray and Northern analysis to assess the changes in gene expression that preceded tumor involution. Of the 1,176 genes on the microarray, 7 were up-regulated, whereas 40 were decreased by TH. Many of these were neuroendocrine in nature and related to growth or apoptosis. When we examined transcripts for cell cycle regulators only cyclin-dependent kinase 2, cyclin A and p57 were down-regulated, whereas p15 was induced by TH. Retinoblastoma protein, c-myc, and mdm2 were unchanged, but E2F1 was down-regulated. TH also decreased expression of brain-derived neurotrophic factor, its receptor trkB, and the receptor for TRH. These, in addition to two other genes, neuronatin and PB cadherin, which were up- and down-regulated, respectively, showed a more rapid response to TH than the cell cycle regulators and may represent direct targets of TH. Finally, p19ARF was dramatically induced by TH, and although this protein can stabilize p53 by sequestering mdm2, we found no increase in p53 protein up to 48 h of treatment. In summary, we have described early changes in the expression of genes that may play a role in TH-induced growth arrest of a thyrotropic tumor. These include repression of specific growth factor and receptors and cell cycle genes as well as induction of other factors associated with growth arrest and apoptosis.
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PMID:Early gene expression changes preceding thyroid hormone-induced involution of a thyrotrope tumor. 1179 85

Karyotypic alterations, including whole chromosome loss or gain, ploidy changes, and a variety of chromosome aberrations are common in cancer cells. If proliferating cells fail to coordinate centrosome duplication with DNA replication, this will inevitably lead to a change in ploidy, and the formation of monopolar or multipolar spindles will generally provoke abnormal segregation of chromosomes. Indeed, it has long been recognized that errors in the centrosome duplication cycle may be an important cause of aneuploidy and thus contribute to cancer formation. This view has recently received fresh impetus with the description of supernumerary centrosomes in almost all solid human tumors. As the primary microtubule organizing center of most eukaryotic cells, the centrosome assures symmetry and bipolarity of the cell division process, a function that is essential for accurate chromosome segregation. Centrosomes undergo duplication precisely once before cell division. Recent reports have revealed that this process is linked to the cell division cycle via cyclin-dependent kinase (cdk) 2 activity that couples centriole duplication to the onset of DNA replication at the G(1)/S phase transition. Alterations of regulatory G(1)/S phase proteins like the retinoblastoma protein, cyclins D and E, cdk4 and 6, cdk inhibitors p16( INK4A ) and p15( INK4B ), and p53 are among the most frequent aberrations observed in human malignancies. These alterations might not only lead to unrestrained proliferation but also cause karyotypic instability by uncontrolled centrosome replication. Since several excellent reports on cell cycle regulation and cancer have been published, this review will focus on causes and consequences of aberrant centrosome replication in human neoplasias.
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PMID:Centrosome aberrations and cancer. 1179 8

The clinical, histological, phenotypic and genotypic features of a lymphoblastoid natural killer (NK)-cell lymphoma presenting in the skin in a young caucasian woman are described. The disease behaved aggressively, but long-lasting remission was obtained by combination chemotherapy followed by autologous bone marrow transplantation. The blastoid cells were positive for terminal deoxynucleotidyl transferase, CD34, CD56 and CD4. Furthermore, the NK-cell receptor complex CD94/NKG2 was strongly expressed, as shown by examination with reverse transcription-polymerase chain reaction. The T-cell receptor (TCR)-gamma genes were in germline, and with the exception of CD4 all T-cell antigens were negative, including CD3, TCR-beta, TCR-delta, TIA-1, granzyme B and perforin. Epstein-Barr virus was negative, and no expression was seen of myeloid cell-associated markers. Molecular analysis showed no abnormalities of the CDKN2A (p16), CDKN2B (p15) or TNFRSF6 (Fas) genes. By contrast, a 34-bp deletion in exon 7 of the TP53 (p53) gene was detected. It is suggested that lymphoblastoid NK-cell lymphoma, which is a rare but distinctive disease, originates from NK cell precursors and may be associated with and possibly caused by alterations in the TP53 gene. Experience is too limited to warrant therapeutic suggestions. However, stem cell transplantation may be a useful option in younger patients.
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PMID:A case of lymphoblastoid natural killer (NK)-cell lymphoma: association with the NK-cell receptor complex CD94/NKG2 and TP53 intragenic deletion. 1184 84


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