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)

In the present study we investigated the prognostic relevance of molecular and immunological changes in pancreatic carcinoma. 82 tissue specimens of adenocarcinoma of the pancreas were stained immunohistochemically with following factors: p53, p21WAF1, Cyklin D, EGF, EGF-R, cERB-B2, CD95, BCL-2 and Cathepsin D. We further determined the serum levels of sCD44, sCD44v6, neopterin and IL-2R. Except Cyclin D none of the immunohistochemically determined factors had prognostic significance. Interestingly all of the immunological serum parameters were of high prognostic significance. These data demonstrate the prognostic relevance of immunological parameters in human adenocarcinoma of the pancreas and could raise the possibility of an early immunological intervention in pancreatic cancer.
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PMID:[Prognostic value of molecular biologogy and immunologic parameters in human pancreatic carcinoma]. 1451 15

Cyclin-dependent protein kinases play important roles in cell cycle progression and are attractive targets for the design of anti-proliferative drugs. Two distinct synthetic CDK1/2 inhibitors, Roscovitine and NU2058, are pharmacologically distinct in their ability to modify p53-dependent transcription and perturb cell cycle progression. Although such active-site CDK1/2 inhibitors comprise the most standard type of enzyme inhibitor, many protein kinases are proving to harbour high affinity docking sites that may provide a potentially novel interface for the design of kinase-inhibitors. We examined whether CDK2 has a docking site for its oligomeric substrate p53, whether small-peptide leads can be developed that inhibit CDK2 function, and whether such peptide-inhibitors are pharmacologically distinct from Roscovitine or NU2058. A docking site for CDK2 was identified in the tetramerization domain of p53 at a site that is distinct from the phospho-acceptor site. Peptides derived from the tetramerization domain of p53 block CDK2 phosphorylation and identification of critical CDK2 contacts in the tetramerization domain of p53 suggest that kinase docking does not require tetramerization of the substrate. Transient transfection assays were developed to show that the GFP-CDK2 docking site fusion protein (GFP-CIP) attenuates p53 activity in vivo and suppresses p21WAF1 induction which is similar to NU2058 but distinct from Roscovitine. A stable cell line with an inducible GFP-CIP gene attenuates p53 activity and induces significant cell death in a drug-resistant melanoma cell line, sensitizes cells to death induced by Doxorubicin, and suppresses cell growth in a colony formation assay. These data indicate that CDK2, in addition to cyclin A, can have a high affinity docking site for a substrate and highlights the possibility that CDK2 docking sites may represent effective targets for inhibitor design.
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PMID:The development of a CDK2-docking site peptide that inhibits p53 and sensitizes cells to death. 1465 72

In the present study, correlations between the oocyte messenger RNA (mRNA) stockpile of Cyclin B, insulin-like growth factor I (IGF-I), insulin-like growth factor (IGF-II), insulin-like growth factor receptor Ib (IGFR Ib), and p53 transcripts and the developmental competence of the oocyte were studied. For this purpose, post-ovulatory ageing was used as a tool to generate oocytes of varying developmental competence. Mature female rainbow trout were held at 12 degrees C and periodically checked for ovulation. Oocytes were collected from each female at ovulation and 5, 14, 21 days later. For each collected egg batch, the abundance of several mRNAs in the oocyte was analyzed by real-time PCR and embryo development was monitored after fertilization. Egg quality was estimated not only through embryonic survival but also by studying the occurrence of specific morphological abnormalities. The present study showed that oocyte post-ovulatory ageing was associated with variations of the relative abundance of several studied transcripts within the oocyte. In addition, the abundance of specific mRNAs could be correlated with either the embryonic survival or the occurrence of malformations. Thus, the abundance of IGFR Ib and Cyclin B transcripts in the oocyte was correlated with the occurrence of morphological abnormalities observed at yolk-sac resorption (negatively for IGFR Ib and positively for Cyclin B), while the maternal stockpile of IGF-I, IGF-II, and IGFR Ib mRNAs was positively correlated with embryonic survival.
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PMID:Messenger RNA stockpile of cyclin B, insulin-like growth factor I, insulin-like growth factor II, insulin-like growth factor receptor Ib, and p53 in the rainbow trout oocyte in relation with developmental competence. 1469 27

Cyclin-dependent kinases (CDKs) have recently raised considerable interest in view of their key role in the regulation of the cell cycle progression. In proliferating cells, distinct CDKs associated with specific cyclins coordinate in an orchestrated way the appropriate transition between different phases of the cell cycle. Mutations and/or aberrant expression of distinct CDKs and their regulatory components lead to uncontrolled proliferation and finally to carcinogenesis. However, in post-mitotic neurons, all CDKs with the exception of CDK5 are silent. CDK5, a proline-directed serine/threonine kinase exhibiting a close structural homology to the mitotic CDKs, binds to p35, the neuron-specific regulatory subunit of CDK5. CDK5 is very abundant in mature neurons and seems to regulate neurotransmitter release through phosphorylation and down-regulation of calcium channel activity. Therefore, the inhibition of CDKs in neurons after oxidative stress and in neurodegenerative disorders has a protective action. Selective CDKs inhibitors were developed as promising drugs for cancer therapy due to their ability to arrest cell cycle progression. The aim of this study was to compare the anti-proliferative effect of roscovitine (ROSC), a potent CDKs inhibitor, with that of cisplatin (CP) on human breast cancer MCF-7 cells. ROSC exerted stronger inhibitory effect on proliferation and cell cycle progression of MCF-7 than CP. Accumulation of G(2)/M arrested cells starting 6 h after onset of ROSC treatment coincided with a strong up-regulation of the p53. Reconstitution with caspase-3 sensitized MCF-7 cells to CP action. It implicates that ROSC inhibits more selectively and efficaciously the proliferation of human breast carcinoma cells.
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PMID:Dual action of cyclin-dependent kinase inhibitors: induction of cell cycle arrest and apoptosis. A comparison of the effects exerted by roscovitine and cisplatin. 1470 84

Inflammatory fibroid polyps (IFPs) are rare mesenchymal tumors of the gastrointestinal tract that consist of spindle-shaped stromal cells and an inflammatory infiltrate rich in eosinophils. Their etiology and histogenesis remain unknown. Based on previous reports of their immunoreactivity for CD34 and c-kit biomarkers, IFPs have been thought to be related to gastrointestinal stromal tumors (GISTs). After reviewing the current literature and examining IFPs at the light microscopic level, we evaluated a series of IFPs using an extensive panel of immunohistochemical and in situ hybridization markers in an effort to gain insight into their etiology and histogenesis and to determine their true relationship to GISTs. Sixteen routinely processed IFP specimens (14 gastric, 1 ileal, and 1 rectal) were immunohistochemically stained for antibodies to CD34, HMB-45, desmin, smooth muscle actin, calponin, h-caldesmon, anaplastic lymphoma kinase, S-100 protein, epithelial membrane antigen, c-kit (CD117), stem cell factor (SCF/N19 or kit ligand), p53, bcl-2, cyclin D1, and human herpesvirus-8 (HHV8). In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) was also performed. Ten cases were further evaluated for the dendritic cell markers fascin, CD21, CD23, and CD35. Stromal cells were diffusely positive for CD34 and fascin in all (100%) cases, and these stromal cells were, in addition, immunoreactive for calponin and smooth muscle actin in 88% and 25% of cases, respectively. CD35 was also found to be focally reactive in the stromal cells. Cyclin-D1 was overexpressed in all (100%) IFPs. All other immunohistochemical markers and EBER were negative in the stromal cells. These findings suggest that the proliferating stromal cells in IFPs are of dendritic cell origin, with some cases also exhibiting myofibroblastic features. Absence of c-kit, SCF, and h-caldesmon immunoreactivity fails to support a relationship to GISTs. We also conclude that Epstein Barr virus and HHV8 are unlikely etiologic agents of IFPs. Overexpression of cyclin D1 in all cases suggests that a defect in cell-cycle regulation may be involved in the growth of IFPs.
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PMID:Inflammatory fibroid polyps of the gastrointestinal tract: evidence for a dendritic cell origin. 1470 72

Teratogen-induced alterations in gene expression play an important role in the genesis of malformations in animals. The recent development of DNA microarrays now offers the opportunity to monitor global changes in gene expression and therefore the potential to obtain significant new information concerning both normal and abnormal development. RNA was isolated from day-9 mouse embryos at 1 and 5 h after exposure to hyperthermia (HS) or 4-hydroperoxycyclophosphamide (4CP) and compared to RNA isolated from concurrent controls using mouse cDNA microarrays. Cy5/Cy3 intensity data were extracted using Spot-on Image software and then normalized using the statistical software program R/maanova. Differentially expressed genes were identified using a linear mixed-effects model and p values derived from t-test statistics. Approximately 9000 genes show statistically significant alterations in expression in day-9 mouse embryos exposed to HS or 4CP. HS and 4CP also induce alterations in the expression of distinct sets of genes, e.g., DNA replication/repair, cell cycle, signal transduction, and transcription-related genes. As expected, a variety of heat shock genes are upregulated by HS but not 4CP. Among genes whose expression is altered by both HS and 4CP, cluster analysis identified three p53 target genes (Cyclin G1, Gtse1, and Mdm2), and follow up studies confirmed that p53 is activated in embryos exposed to these two teratogens. In addition, cluster analyses also revealed that HS but not 4CP induces the downregulation of genes encoding key enzymes in the cholesterol biosynthesis pathway. Thus, our microarray data have identified one potentially important pathway (p53) common to both HS- and 4CP-induced teratogenesis and another pathway (cholesterol biosynthesis) potentially important, but specific to HS-induced teratogenesis.
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PMID:Alterations in gene expression induced in day-9 mouse embryos exposed to hyperthermia (HS) or 4-hydroperoxycyclophosphamide (4CP): analysis using cDNA microarrays. 1497 50

We applied comparative genomic hybridization (CGH) to 46 breast carcinoma samples, collected from 1993 to 1995, in order to detect chromosome 1q gains and 16q losses and to define whether samples showing both these alterations had distinct biopathologic features and different clinical outcome. A total of 22 samples (48%) had simultaneous chromosome 1q gain and 16q loss, which was always associated with other genetic changes. In total, 23 samples had various chromosome imbalances (including chromosome 1q gain independent of chromosome 16q loss and vice versa) and one sample did not show detectable alterations. Samples having chromosome 1q gain/16q loss were compared to the other samples with regard to neoplasm size, lymph-node status, histologic and nuclear grade, estrogen and progesterone receptor presence, Ki-67, pRB, Cyclin D1, Cyclin A, p53, p21 and p27 expression as detected by immunohistochemistry. The samples showing chromosome 1q gain/16q loss had high steroid hormone receptor expression (P=0.02), low cell growth fraction (Ki-67, P=0.03) and high p27 expression (P<0.001). No statistical correlation with disease-free survival and overall survival or response to hormonal therapy was found. We conclude that simultaneous chromosome 1q gain/16q loss is a frequent event in invasive breast cancer, which occurs in a subset of both intermediate- and high-grade breast carcinomas. Although the final chromosome 1q and 16q imbalances might have originated from different chromosome alterations in low- and high-grade samples, the gene-dosage effect might be important in conferring peculiar biopathologic characteristics to this subset of samples. The cytogenetic and molecular mechanisms underlying these chromosome changes deserve further investigations.
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PMID:Simultaneous chromosome 1q gain and 16q loss is associated with steroid receptor presence and low proliferation in breast carcinoma. 1497 37

Cyclin G is one of the earliest p53 target genes to be identified, but its function in the p53 pathway has been elusive. Although the precise mechanisms of cyclin G in this novel network have not been explored, recent studies have demonstrated that cyclin G is a key regulator of the p53-Mdm2 network. Here we present evidence that cyclin G-mediated p53 regulation is dependent upon the status of ataxia-telangiectasia mutated (ATM) protein, which activates p53 in response to DNA damage. Abrogation of cyclin G enhances p53 accumulation and phosphorylation of p53 at the Ser-15 residue, resulting in cell cycle arrest. Ectopically expressed cyclin G significantly reduces the steady-state levels of p53 as well as that of phosphorylated p53 at Ser-15 after DNA damage in normal human dermal fibroblasts containing normal ATM. However, cyclin G does not cause similar reductions in p53 levels in ATM-mutated cells. We also show that translocation of cyclin G to the nucleus requires functional ATM. Thus, our findings identify a new role of cyclin G in ATM-dependent p53 regulation and in cell cycle regulation during DNA damage.
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PMID:The negative role of cyclin G in ATM-dependent p53 activation. 1507 71

In early cervical intraepithelial neoplasia (CIN), the Ki67 stratification index 90th percentile (Si90) is a strong predictor of progression. This study was designed to further investigate the mechanisms leading to elevated Ki67 levels in lesions that progress and to try to improve the prognostic accuracy of Ki67-Si90. We studied 90 CIN lesions in which consensus existed regarding the grade between two experienced gynecologic pathologists. All CINs were p16-positive and showed Ki67 cell clusters above the lower third of the epithelium (both features diagnostic for CIN). Ki67 parameters, cell cycle regulators (Rb, p53, Cyclin A, E and D, p16, p21, p27, and telomerase), and cellular differentiation products (involucrin, CK13, CK14) were compared in the basal zone as well as the deeper and upper halves of the epithelium. Fifteen CIN cases (17%) progressed to a higher CIN grade, including 2 of 25 CIN1 (8%) and 13 of 65 CIN2 (20%) (these proportions of progressing CINs are similar to those in a large meta-analysis). Ki67 quantitation effectively predicted CIN progression as 0 of 40 "Ki67 low-risk" and 15 of 50 (30%) "Ki67 high-risk" lesions progressed. CIN progressors showed decreased Rb, CK13, CK14, and involucrin, but increased p21 and p27 expression. Ki67-Si90 and Rb in the deeper half of the epithelium (RbDeep) were the strongest multivariate independent predictors of progression. Ki67-Si90>0.57 was unfavorable, but only if it coexisted with RbDeep <45% (progression risk = 47%). All early CINs with combined Si90>0.57+RbDeep>45% or any Ki67-Si90 value below 0.57 were nonprogressors. In the high-risk progression subgroup (Ki67-Si90>0.57+RbDeep<45%), all cases with combined CK14<50% and CK13<80% (both in the basal cell layer) (4% of all lesions) progressed. We hypothesize that onco-HPV E7 expression reduces Rb, causing increased and upward proliferation (Ki67-Si90>0.57). Increased RbDeep can reduce proliferation, including its upward spread. Combined quantitation of Ki67, Rb, CK13, and CK14 gives accurate information about the progression risk of early CIN lesions.
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PMID:Quantitative molecular parameters to identify low-risk and high-risk early CIN lesions: role of markers of proliferative activity and differentiation and Rb availability. 1508 35

Cell cycle is one of the most complex processes in the life of a dividing cell. It involves numerous regulatory proteins, which direct the cell through a specific sequence of events for the production of two daughter cells. Cyclin-dependent kinases (cdks), which complex with the cyclin proteins, are the main players in the cell cycle. They can regulate the progression of the cells through different stages regulated by several proteins including p53, p21(WAF1), p19, p16, and cdc25. Downstream targets of cyclin-cdk complexes include pRB and E2F. A cell cycle can be altered to the advantage of many viral agents, most notably polyomaviruses, papillomaviruses, adenoviruses, and retroviruses. In addition, viral protein R (Vpr) is a protein encoded by the human immunodeficiency virus type 1 (HIV-1). HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), is a member of the lentivirus class of retroviruses. This accessory protein plays an important role in the regulation of the cell cycle by causing G(2) arrest and affecting cell cycle regulators. Vpr prevents infected cells from proliferating, and collaborates with the matrix protein (MA) to enable HIV-1 to enter the nucleus of nondividing cells. Studies from different labs including ours showed that Vpr affects the functions of cell cycle proteins, including p53 and p21(WAF1). Thus, the replication of HIV-1, and ultimately its pathogenesis, are intrinsically tied to cell-cycle control.
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PMID:Effect of HIV-1 Vpr on cell cycle regulators. 1514 82


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