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

The hallmark of Epstein-Barr virus (EBV) infection is the establishment of a viral genome transcription pattern called latency. The EBV BZLF1 gene product EB1 (also known as ZEBRA or Zta) is a transcription factor which is essential for the switch from latency to the lytic cycle. It has been proposed that latency is maintained (i) by the inhibition of EB1 translation via antisense hybridization of EBNA1 and EB1 hnRNAs, or (ii) by the inactivation of the EB1 activating function via the direct interaction of EB1 with RelA, the retinoic acid receptor and p53, or via the titration of EB1 in RAZ:EB1 inactive heterodimers that are unable to bind to DNA. RAZ, a fusion protein which contains the EB1 C-terminal dimerization and DNA-binding domains fused to the N-terminal 86 amino acids of the EBV BRLF1 gene product R, has been described as a trans-dominant negative regulator of EB1-activated transcription. We demonstrate here that although RAZ efficiently represses EB1-mediated transcriptional activation, the amount of RAZ protein expressed is incompatible with repression through the titration of EB1 in inactive EB1:RAZ heterodimers. Furthermore, we also demonstrate that RAZ efficiently represses transcription activated by an EB1 mutant carrying the GCN4 homodimerization domain (EB1 gcn4), despite the inability of RAZ and EB1 gcn4 to form stable heterodimers.
 ...
PMID:Repression by RAZ of Epstein-Barr virus bZIP transcription factor EB1 is dimerization independent. 875 96

Testicular germ tumor cells could be differentiated spontaneously or by some chemotherapeutic compounds. However, the mechanism by which the cells are differentiating from the stem cell remains unclear. The KU-MT cells, which were newly established from lung metastasis of testicular carcinoma, have been continuously producing alpha fetoprotein (AFP). Retinoic acids are well-known to induce cellular differentiation in culture and have already been applied for a clinical usage against leukemia. In the present study, all-trans-retionic acid (ATRA) elevated the level of AFP and inhibited the growth of KU-MT cells in vitro. ATRA also arrested the cell cycle in G1 and reduced the percentage of the S phase cell in terms of wild type p53, leading to apoptosis in part. Retinoids, especially retinoic acid receptor (RAR)-alpha specific agonists induced laminin production, a marker of endodermal differentiation; whereas arotinoid, a retinoid not bound to RAR-alpha, did not affect laminin expression. In summary, retinoic acids could mediate cell growth and differentiation of testicular tumor through RAR-alpha.
 ...
PMID:[Retinoic acid-induced cell growth inhibition and differentiation in testicular carcinoma cells in culture]. 943 34

The mdm2 gene is positively regulated by p53 through a p53-responsive DNA element in the first intron of the mdm2 gene. mdm2 binds p53, thereby abrogating the ability of p53 to activate the mdm2 gene, and thus forming an autoregulatory loop of mdm2 gene regulation. Although the mdm2 gene is thought to act as an oncogene by blocking the activity of p53, recent studies indicate that mdm2 can act independently of p53 and block the G1 cell cycle arrest mediated by members of the retinoblastoma gene family and can activate E2F1/DP1 and the cyclin A gene promoter. In addition, factors other than p53 have recently been shown to regulate the mdm2 gene. In this article, we report that thyroid hormone (T3) receptors (T3Rs), but not the closely related members of the nuclear thyroid hormone/retinoid receptor gene family (retinoic acid receptor, vitamin D receptor, peroxisome proliferation activation receptor, or retinoid X receptor), regulate mdm2 through the same intron sequences that are modulated by p53. Chicken ovalbumin upstream promoter transcription factor I, an orphan nuclear receptor which normally acts as a transcriptional repressor, also activates mdm2 through the same intron region of the mdm2 gene. Two T3R-responsive DNA elements were identified and further mapped to sequences within each of the p53 binding sites of the mdm2 intron. A 10-amino-acid sequence in the N-terminal region of T3Ralpha that is important for transactivation and interaction with TFIIB was also found to be important for activation of the mdm2 gene response element. T3 was found to stimulate the endogenous mdm2 gene in GH4C1 cells. These cells are known to express T3Rs, and T3 is known to stimulate replication of these cells via an effect in the G1 phase of the cell cycle. Our findings, which indicate that T3Rs can regulate the mdm2 gene independently of p53, provide an explanation for certain known effects of T3 and T3Rs on cell proliferation. In addition, these findings provide further evidence for p53-independent regulation of mdm2 which could lead to the development of tumors from cells that express low levels of p53 or that express p53 mutants defective in binding to and activating the mdm2 gene.
 ...
PMID:Regulation of the mdm2 oncogene by thyroid hormone receptor. 985 9

Uncontrolled proliferation and a defect of apoptosis constitute crucial elements in the development and progression of tumours. Among many other biological response modifiers known to influence these mechanisms, the efficacy of retinoids and interferons in the treatment of various malignant entities is currently matter of discussion. In the present study, we have investigated the effects of 9-cis-retinoic acid (9cRA), 13-cis-retinoic acid (13cRA), all-trans-retinoic acid (tRA) and interferon-alpha on proliferation and apoptosis of human soft tissue sarcoma (STS) cell lines HTB-82 (rhabdomyosarcoma), HTB-91 (fibrosarcoma), HTB-92 (liposarcoma), HTB-93 (synovial sarcoma) and HTB-94 (chondrosarcoma) in relation to p53 genotype as well as p53 expression. HTB-91, HTB-92 and HTB-94 STS cells exhibited mutant p53, whereas wild-type p53 was found in HTB-93 STS cells, and a normal p53 status in HTB-82 STS cells, carrying a silent point mutation only. Interferon-alpha, irrespective of p53 status, inhibited the proliferation of all five cell lines dose- and time-dependently. Similarly, 9cRA, 13cRA and tRA decreased the proliferation of HTB-82 and HTB-93 STS cells, whereas the proliferation of p53-mutated HTB-91, HTB-92 and HTB-94 STS cells remained unchanged. Furthermore, only 9cRA and tRA were capable of inducing apoptosis in HTB-82 and HTB-93 STS cells, whereas HTB-91, HTB-92 and HTB-94 STS cells did not undergo apoptosis under the influence of 9cRA or tRA. Retinoic acid receptor (RAR)-alpha and RAR-beta mRNA were not detectable by Northern blot analysis in the five STS cell lines, whereas mRNA for the universal retinoic acid receptor, RAR-gamma, was expressed in all STS cell lines indicating that retinoid resistance was not associated with a lack of RAR expression. Apoptosis was not induced by interferon-alpha or 13cRA in any of the five STS cell lines tested. Our results indicate that within the panel of tested STS cell lines, inhibition of proliferation and induction of apoptosis result from different mechanisms which differ in their dependence upon the presence of intact p53.
 ...
PMID:Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-alpha and retinoids. 1042 35

Smoking prevention will decrease lung cancer incidence in time. However, early detection would improve lung cancer prognosis in subjects at risk provided that specific markers could be identified. We previously reported that retinoic acid receptor (RAR) and retinoid X receptor (RXR) expression was altered in lung tumors. RAR-beta gene status could be derived from corresponding allelotyping and immunohistochemistry data. We now report the continued study on lung cancer precursor lesions. Fluorescence PCR-based assays were used for allelotyping at the RAR/RXR loci of: (a) 66 lung precursor lesions found at the free resection margins of 41 patients undergoing surgery for lung cancer (+ 31 paired tumors); and (b) bronchial cells also found at the free resection margins from 16 current and 8 never smokers operated on for noncancerous diseases. Three microsatellites located at 3p14-21 and 9p21 were also used for interwork comparison. Immunohistochemistry was additionally performed to evaluate P53 and RAR-beta expression in precursor lesions. Chi2 tests showed significant differences (P < 0.05) when comparing the results obtained from never smokers, smokers, squamous metaplasia, dysplasia + in situ carcinoma, and tumors. Microsatellite changes occurred frequently in all samples, but without specificity for any group (P < 0.08-0.52). They were globally correlated with tobacco exposure (P < 0.04), for which the RAR-gamma marker appeared as a preferential target (P < 0.004). Few reparation error phenotypes were observed, mostly at the RXR-alpha and RXR-gamma markers for which combined changes were also linearly increasing from never smokers to dysplasia + in situ carcinoma (P < 0.05 and P < 0.03). RAR-beta marker losses also increased from the first to the last group studied (P < 0.01), with a concomitant decrease in RAR-beta protein expression and correlated p53 increased immunoreactivity (P < 0.02). Losses at 3p14, 3p21, and P16 were frequent, but no significant differences between groups could be found. Unexpectedly, high constitutive homozygosity was observed near the RAR-alpha locus in squamous cell lung cancer cases. RARs/RXRs form homodimers or heterodimers involved in ligand binding. Their added alterations could result in a state of functional vitamin A deficiency in the affected bronchial cells. Further deletion events drawn from a limited repertoire of specific regions such as 3p14-21 and 9p21 could subsequently drive the deficient cells to invasive carcinoma.
 ...
PMID:Retinoic acid receptor and retinoid X receptor alterations in lung cancer precursor lesions. 1085 Apr 30

AMP-activated protein kinase (AMP-kinase) modulates many metabolic processes in response to fluctuations in cellular energy status. Although most of its known targets are metabolic enzymes, it has been proposed that AMP-kinase might also regulate gene expression. Here we demonstrate that the transcriptional coactivator p300 is a substrate of AMP-kinase. Phosphorylation of p300 at serine 89 by AMP-kinase dramatically reduced its interaction, in vitro and in vivo, with the nuclear receptors peroxisome proliferator-activated receptor gamma, thyroid receptor, retinoic acid receptor, and retinoid X receptor, but did not affect its interaction with the non-nuclear receptor transcription factors E1a, p53, or GATA4. These findings indicate that the AMP-kinase signaling pathway selectively modulates a subset of p300 activities and represent the first example of a transcriptional component regulated by AMP-kinase. Our results suggest a direct link between cellular energy metabolism and gene expression.
 ...
PMID:Regulation of transcription by AMP-activated protein kinase: phosphorylation of p300 blocks its interaction with nuclear receptors. 1151 99

A tumor suppressor gene. retinoic acid receptor (RAR) beta2, has been mapped to chromosome 3p24, a region where loss of heterozygosity (LOH) has been observed commonly in carcinomas of various tumor tissues. RAR beta2 expression is reduced or lost in many malignant tumors including breast cancer, however, whether LOH accounts for the loss of expression of RAR beta2 in breast cancer is unknown. We, therefore, assessed LOH on chromosome band 3p24 to correlate it with RAR beta2 expression and other established prognostic parameters in 52 breast carcinomas. Based on three microsatellites, D3S 1283, D3S 1293 and D3S 1286. all of the tumors were informative, of these, 12 (23%) exhibited LOH. RAR beta2 expression was lost in 42% (19/45) of these samples. We found that LOH on chromosome band 3p24 was not correlated with loss of RAR beta2, but correlated with higher histological grade, p53-positivity, and loss of estrogen and progesterone receptors. Our findings suggest that LOH of the RAR beta2 gene does not account for the frequent loss of RAR beta2 expression in breast cancer but the genomic structural alteration at or close to the RAR beta2 gene locus are likely to be associated with tumor progression and/or loss of hormonal dependency.
 ...
PMID:Allelic loss of chromosome 3p24 correlates with tumor progression rather than with retinoic acid receptor beta2 expression in breast carcinoma. 1176 3

Molecular biomarkers for breast cancer are of several types. Risk biomarkers are those associated with increased cancer risk and include mammographic abnormalities, proliferative breast disease with or without atypia, family clustering and inherited germ-line abnormalities. Surrogate endpoint biomarkers are tissue, cellular or molecular alterations that occur between cancer initiation and progression. These biomarkers are utilized as endpoints in short-term chemoprevention trials. Prognostic biomarkers provide information regarding outcome irrespective of therapy, while predictive biomarkers provide information regarding response to therapy. Candidate prognostic biomarkers for breast cancer include elevated proliferation indices such as Ki-67 and proliferating cell nuclear antigen (PCNA); ER and PR overexpression; markers of oncogene overexpression such as c-erbB-2, TGF-a and EGFr; indicators of apoptotic imbalance including overexpression of bcl-2 and an increased bax/bcl-2 ratio; markers of disordered cell signaling such as p53 nuclear protein accumulation; alteration of differentiation signals such as overexpression of c-myc and related proteins; loss of differentiation markers such as TGF-b II receptor and retinoic acid receptor; and alteration of angiogenesis proteins such as VEGF overexpression. As our knowledge regarding molecular biomarkers for breast cancer increases, prognostic indices will be developed that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors.
 ...
PMID:Biomarkers for breast cancer. 1214 73

This study has identified molecular changes characteristic of early oral cancer progression. We reported previously that acquisition of the immortal phenotype is an early event in oral cancer development (F. McGregor et al., Cancer Res., 57: 3886-3889, 1997); our current data indicate that about half of oral dysplasia cultures are immortal, and this is associated with loss of expression of retinoic acid receptor (RAR)-beta and the cell cycle inhibitor p16(ink4a) (p16), p53 mutations, and increased levels of telomerase/human telomerase reverse transcriptase mRNA. In contrast, increased expression of the epidermal growth factor receptor, known to be a characteristic of oral cancer, does not occur until after the dysplasia stage in squamous cell carcinomas. Acquisition of invasive properties as judged by an in vitro Matrigel invasion assay also does not occur until the carcinoma stage and is further increased in metastases. Interestingly, one atypical mortal dysplasia with a considerably extended life span has lost expression of RAR-beta and p16, but it still expresses only wild-type p53 (albeit at a higher level than normal) and has not activated telomerase. RAR-beta and/or p16 re-expression can be induced by treatment with 5-aza-2-deoxycytidine (Aza-C) in some immortal dysplasias, and this has been shown to be due to silencing of gene expression by promoter methylation. Aza-C treatment also down-regulated telomerase activity and human telomerase reverse transcriptase mRNA. Interestingly, with one dysplasia, Aza-C was able to reverse its immortal phenotype, as judged by morphological criteria and expression of the senescence-associated acid beta-galactosidase activity during terminal growth arrest; this immortal dysplasia was the only one in which Aza-C treatment not only down-regulated telomerase activity but also induced re-expression of both RAR-beta and p16. The possibility of reversing the immortal phenotype of some dysplasias by Aza-C may be of clinical usefulness.
 ...
PMID:Molecular changes associated with oral dysplasia progression and acquisition of immortality: potential for its reversal by 5-azacytidine. 1218 35

Hypermethylation of CpG islands in gene promoters is associated with silencing of various tumour suppressor genes. Recent studies of colorectal and gastric carcinomas have defined a CpG island methylator phenotype (CIMP), which involves the targeting of multiple genes by promoter hypermethylation. In this study, methylation-specific polymerase chain reaction (PCR) was performed to study methylation of CpG islands in the promoters of the p16(INK4a), cadherin 1 (CDH1), and retinoic acid receptor-beta (RAR-beta) genes in 45 gastric carcinomas and to investigate whether CDH1 and RAR-beta promoter hypermethylation is associated with CIMP-positive gastric carcinoma. CpG island hypermethylation of the p16(INK4a), CDH1, and RAR-beta promoters was detected in 12 (27%), 26 (58%), and 24 (53%) of the 45 gastric carcinomas, respectively. Hypermethylation of the p16(INK4a) promoter was more common in intestinal type than in diffuse type gastric carcinomas (p = 0.0023; Fisher's exact test) and was inversely associated with p53 mutations (p = 0.0225; Fisher's exact test). However, CDH1 and RAR-beta promoter hypermethylation was observed more frequently in diffuse-scattered type gastric carcinoma than in other types (intestinal and diffuse-adherent types) (p = 0.0175 and p = 0.0335, respectively; Fisher's exact test) and was not associated with p53 mutation status. Moreover, hypermethylation of the CDH1 and RAR-beta promoters occurred concordantly (p < 0.0001; Fisher's exact test). These results suggest that at least two types of promoter methylation status are involved in the development of the intestinal (p16(INK4a) promoter hypermethylation) and diffuse-scattered types (CDH1 and RAR-beta promoter hypermethylation) of gastric carcinoma.
 ...
PMID:Distinct promoter hypermethylation of p16INK4a, CDH1, and RAR-beta in intestinal, diffuse-adherent, and diffuse-scattered type gastric carcinomas. 1221 63


1 2 3 4 Next >>