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)

Aragusterol A (YTA0040), isolated from the Okinawan marine sponge of the genus Xestospongia, is a potent anti-tumor marine steroid that possesses a unique structural component. This compound showed broad-spectrum anti-proliferative activity against a panel of 14 human cancer cell lines (IC(50) = 0.01-1.6 microM). P-glycoprotein-mediated, multidrug-resistant cells showed cross-resistance to YTA0040 cells, whereas cisplatin-resistant non-small-cell lung-cancer (NSCLC) sublines showed a collateral sensitivity to YTA0040. In transplantable murine tumor models, YTA0040 displayed a broad spectrum and high degree of anti-tumor activity when administered i.p. or p.o. (life span T/C = 135-234%). In P388 murine leukemia cells, YTA0040 caused dose- and time-dependent suppression of nucleic acid and protein synthesis, with protein synthesis being more potently and rapidly inhibited than nucleic acid synthesis. Flow-cytometric analysis revealed that YTA0040 blocked the entry of human NSCLC-derived A549 cells into S phase, leading to arrest in the G(1) phase of the cell cycle. Western blot analysis demonstrated that YTA0040 caused a dose-dependent decrease in the levels of expression of hyperphosphorylated pRb and cyclin A in A549 cells. The level of p53 protein expression was decreased by YTA0040 treatment. A higher concentration of YTA0040 down-regulated the levels of expression of CDK2, CDK4, cyclin D1 and cyclin E. These findings indicated that YTA0040 arrested human NSCLC cells in late G(1) phase of the cell cycle through inhibition of pRb phosphorylation. Inhibition of pRb phosphorylation by YTA0040 resulted from down-regulation of levels of expression of the CDKs and cyclins involved in the G(1)/S transition and not from induction of p53 and/or the CDK inhibitor p21.
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PMID:Mechanism of action of aragusterol a (YTA0040), a potent anti-tumor marine steroid targeting the G(1) phase of the cell cycle. 1107 53

Glioblastoma multiforme (GBM) is the most common primary tumor occurring in the central nervous system of adults. Although progress has been made in clinical management of this tumor, little is known about the molecular defects underlying the initiation and progression of GBM. To address these issues, we have characterized five cases of GBM using cytogenetics, comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and direct sequencing. All of these tumors were observed to have clonal chromosome aberrations. Complicated chromosome translocations including der(18)t(2;4;12;18), der(X)t(X;10)(q27.1;p12.1) and der(10)t(10;15)(p11.23;q11.2), and der(1) (:1p31-->1q44::7q11. 3-->7qter) were seen in three tumors. Loss of the CDKN2 gene was noted in four tumors. A gain of copy number of the Cathepsin L gene was seen in two tumors. Amplification of the CDK4, MDM2, and GLI/CHOP genes was noted in two tumors, and amplification of the PDGFR gene was detected in one tumor. Mutation of exon 5 of the TP53 gene was found in three tumors. No mutation of the BCL10 gene was detected in five cases of GBM analyzed, although deletion of chromosome 1p was seen in two tumors. These results provide information for further investigation of GBM.
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PMID:Molecular and cytogenetic analysis of glioblastoma multiforme. 1110 17

Osteosarcoma is an uncommon tumor. Family occurrence of osteosarcoma is even rarer. Four cases of osteosarcoma in two siblings and in a father and son treated at our Institute with surgery and chemotherapy are reported. These patients had no other tumors in their family history, and had negative p53 mutations in exons 5-9 by SSCP analysis. RB, CDK4, MDM2, c-myc, c-fos, and p53 gene expression, which are the major genes involved in osteosarcoma susceptibility, were studied. Our results revealed an inactive form of p53 sporadically seen in the samples, a total loss of Rb protein expression, an increased expression of Cdk4, MDM2, c-fos, and c-myc proteins which literature currently reports being the principal alterations found in osteosarcoma. These findings confirm that specific genetic alterations occur in osteosarcoma pathogenesis.
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PMID:Osteosarcoma in blood relatives. 1111 84

Replicative senescence of human diploid fibroblasts (HDFs) or melanocytes is caused by the exhaustion of their proliferative potential. Stress-induced premature senescence (SIPS) occurs after many different sublethal stresses including H(2)O(2), hyperoxia, or tert-butylhydroperoxide. Cells in replicative senescence share common features with cells in SIPS: morphology, senescence-associated beta-galactosidase activity, cell cycle regulation, gene expression and telomere shortening. Telomere shortening is attributed to the accumulation of DNA single-strand breaks induced by oxidative damage. SIPS could be a mechanism of accumulation of senescent-like cells in vivo. Melanocytes exposed to sublethal doses of UVB undergo SIPS. Melanocytes from dark- and light- skinned populations display differences in their cell cycle regulation. Delayed SIPS occurs in melanocytes from light-skinned populations since a reduced association of p16(Ink-4a) with CDK4 and reduced phosphorylation of the retinoblastoma protein are observed. The role of reactive oxygen species in melanocyte SIPS is unclear. Both replicative senescence and SIPS are dependent on two major pathways. One is triggered by DNA damage, telomere damage and/or shortening and involves the activation of the p53 and p21(waf-1) proteins. The second pathway results in the accumulation of p16(Ink-4a) with the MAP kinase signalling pathway as possible intermediate. These data corroborate the thermodynamical theory of ageing, according to which the exposure of cells to sublethal stresses of various natures can trigger SIPS, with possible modulations of this process by bioenergetics.
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PMID:Cellular and molecular mechanisms of stress-induced premature senescence (SIPS) of human diploid fibroblasts and melanocytes. 1112 81

Nineteen specimens from primary human malignant mesotheliomas obtained from 19 patients were screened for activating point mutations in the oncogenes N-ras and CDK4 by combined RFLP-PCR/SSCP analysis. In addition, all tumours were screened for deletions and point mutations in the tumour suppressor genes p53, p16INK4a (CDKN2A) and p14ARF (exon-1beta) by combined multiplex-PCR/SSCP analysis. No mutations were found in N-ras, p53 and CDK4. Three tumours displayed homozygous deletion (co-deletion of exons 1, 2 and 3) of p16INK4a. One of them displayed additional homozygous deletion of p14ARF (exon-1beta). Two silent point mutations and 2 polymorphisms were found in p16INK4a in 3 tumours. Our preliminary data indicate that disarrangement of the Rb1 pathway may be involved in mesothelioma formation.
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PMID:Mutational analysis of N-ras, p53, p16INK4a, p14ARF and CDK4 genes in primary human malignant mesotheliomas. 1117 13

Twenty-three cases of basaloid squamous cell carcinoma (BSCC) and 23 stage-matched pairs of typical squamous cell carcinoma (SCC) of the oesophagus were investigated for molecular aberrations. Polymerase chain reaction (PCR) was used to detect loss of heterozygosity at the APC, RB, and MCC gene loci, while differential PCR was carried out to detect amplification of the CDK4 gene. In addition, the level of expression of the p53 and RB proteins in the tumour tissue was assessed by immunohistochemistry. Loss of heterozygosity (LOH) at the APC and MCC loci was about twice as common in BSCC as in SCC (40% vs. 21% and 33% vs. 12%, respectively), with co-existence of LOH at both loci occurring only in BSCC. LOH frequency at the RB gene locus was not remarkably different in either BSCC or SCC (20% vs. 24%, respectively). On immunohistochemistry, accumulation of p53 protein was slightly more frequent in BSCC than in SCC (61% vs. 52%), whereas the rate of loss of RB protein expression was about equal in both types of carcinoma (9% vs. 13% BSCC and SCC, respectively). There was no detectable amplification of the CDK4 gene in either type of tumour. Although the observed differences did not achieve statistical significance, this work has further highlighted possible differences between the molecular pathogenesis of BSCC and SCC.
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PMID:Comparative analysis of basaloid and typical squamous cell carcinoma of the oesophagus: a molecular biological and immunohistochemical study. 1118 Jan 60

We have previously reported that apigenin inhibits the growth of thyroid cancer cells by attenuating epidermal growth factor receptor (EGF-R) tyrosine phosphorylation and phosphorylation of ERK mitogen-activated protein (MAP) kinase. In this study, we assessed the growth inhibitory effect of apigenin on MCF-7 breast carcinoma cells that express two key cell cycle regulators, wild-type p53 and the retinoblastoma tumor suppressor protein (Rb), and MDA-MB-468 breast carcinoma cells that are mutant for p53 and Rb negative. We found that apigenin potently inhibited growth of both MCF-7 and MDA-MB-468 breast carcinoma cells. The approximate IC50 values determined after 3 days incubation, were 7.8 micrograms/ml for MCF-7 cells, and 8.9 micrograms/ml for MDA-MB-468 cells, respectively. Because the cell cycle studies using FACS showed that both MCF-7 and MDA-MB-468 cells were arrested in G2/M phase after apigenin treatment, we studied the effects of apigenin on cell cycle regulatory molecules. We observed that G2/M arrest by apigenin involved a significant decrease in cyclin B1 and CDK1 protein levels, resulting in a marked inhibition of CDK1 kinase activity. Apigenin reduced the protein levels of CDK4, cyclins D1 and A, but did not affect cyclin E, CDK2 and CDK6 protein expression. In MCF-7 cells, apigenin markedly reduced Rb phosphorylation after 12 h. We also found that apigenin treatment resulted in a dose- and time-dependent inhibition of ERK MAP kinase phosphorylation and activation in MDA-MB-468 cells. These results suggest that apigenin is a promising antibreast cancer agent and its growth inhibitory effects are mediated by targeting different signal transduction pathways in MCF-7 and MDA-MB-468 breast carcinoma cells.
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PMID:Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast carcinoma cells. 1129 71

The INK4a/ARF locus on chromosome 9p21 encodes two gene products that are involved in cell cycle regulation through inhibition of CDK4-mediated RB phosphorylation (p16INK4a) and binding to MDM2 leading to p53 stabilization (p14ARF). The locus is deleted in up to 25% of oligodendrogliomas and 50% of anaplastic oligodendrogliomas, but little is known on the frequency of gene silencing by DNA methylation. We assessed promoter hypermethylation of p14ARF and p16INK4a using methylation-specific PCR, and homozygous deletion of the p14ARF and p16INK4a genes by differential PCR in 29 oligodendrogliomas (WHO grade II) and 20 anaplastic oligodendrogliomas (WHO grade III). Promoter hypermethylation of the p14ARF gene was detected in 6/29 (21%) oligodendrogliomas and 3/20 (15%) anaplastic oligodendrogliomas. None of the oligodendrogliomas and only 1 out of 20 anaplastic oligodendrogliomas showed hypermethylation of p16INK4a. Homozygous deletion was not detected in any of the WHO grade II oligodendrogliomas but was present in 5/20 (25%) anaplastic oligodendrogliomas and always affected both genes. In one tumor containing distinct areas with and without anaplasia, p14ARF hypermethylation was detected in the WHO grade II area, while homozygous co-deletion of p14ARF and p16INK4a was found in the region with anaplastic features (grade III). These data suggest that aberrant p14ARF expression due to hypermethylation is the earliest INK4a/ARF change in the evolution of oligodendrogliomas, while the presence of p14ARF and p16INK4a deletions indicates progression to anaplastic oligodendroglioma.
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PMID:Promoter hypermethylation and homozygous deletion of the p14ARF and p16INK4a genes in oligodendrogliomas. 1130 15

Phosphorylation of the product of the retinoblastoma susceptibility gene (Rb) physiologically inactivates its growth-suppressive properties. Rb phosphorylation is mediated by cyclin-dependent kinases (CDKs), whose activity is enhanced by cyclins and inhibited by CDK inhibitors. p16(INK4A) is a member of a family of inhibitors specific for CDK4 and CDK6. p16(INK4A) is deleted and inactivated in a wide variety of human malignancies, including familial melanomas and pancreatic carcinoma syndromes, indicating that it is an authentic human tumor suppressor. Although one mechanism for its tumor suppression may be prevention of Rb phosphorylation, thereby causing G1 arrest, many normal cell types express p16(INK4A), and are still able to traverse the cell cycle. In a search for other mechanisms, we have found that p16(INK4A) is required for p53-independent G1 arrest in response to DNA-damaging agents, including topoisomerase I and II inhibitors. Thus, like other tumor suppressors, p16(INK4A) plays an essential role in a DNA-damage checkpoint that leads to cell cycle arrest.
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PMID:The physiology of p16(INK4A)-mediated G1 proliferative arrest. 1132 39

We report here for the first time, that the SV40 small t-antigen inhibits mammary gland differentiation during mid-pregnancy and that about 10% of multiparous WAP-SVt transgenic animals develop breast tumors with latencies ranging from 10-17 months. Cyclin D1 is deregulated and over expressed in the small t-antigen positive mammary gland epithelial cells (ME-cells) and in the breast tumor cells. SV40 small t-antigen immortalized ME-cells (t-ME-cells) exhibit a strong intranuclear cyclin D1 staining, also in the absence of external growth factors and the cells continue to divide for several days without serum. In addition, the expression rate of cyclin E and p21(Waf1) but not of p53 is increased. Coimmunoprecipitation experiments revealed that p21(Waf1) is mainly associated with the cyclin D/CDK4 but not with the cyclin E/CDK2 complex. WAP-SVT transgenic animals exhibit an almost regular mammary gland development until late pregnancy but the majority of the ME-cells are eliminated by apoptosis during the early lactation period. Tumor formation is delayed and less efficient than in T/t-antigen positive animals. Sequestration of p53 and pRb by the N-terminal truncated T-antigen molecules (T1-antigen and T2-antigen) does not affect mammary gland differentiation and the transgenic animals (WAP-SVBst-Bam) do not develop breast tumors.
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PMID:The SV40 small t-antigen prevents mammary gland differentiation and induces breast cancer formation in transgenic mice; truncated large T-antigen molecules harboring the intact p53 and pRb binding region do not have this effect. 1140 28


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