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)

We have analyzed the expression of the CDKN1A (p21(CIP1)), CDKN1B (p27(Kip1)), TP53, RB1 and MDM2 proteins and tumor cell proliferation by immunohistochemical staining in 59 cases of metastatic melanoma. The genomic status of the CDKN2A (INK4-ARF, p16/p14(ARF)), CDKN2B (p15) and CDKN2C (p18) genes was determined by PCR-SSCP (single-strand conformation polymorphism) in 46 of these cases. These results were correlated with various clinico-pathological parameters, including the outcome of combined chemoimmunotherapy. We found positive correlations between the expression of CDKN1A and MDM2 (r = 0.5063, P = 0.001), between the expression of CDKN1B and RB1 (r = 0.5026, P = 0.001), and between RB1 expression and tumor cell proliferation (0.5564, P<0.001). Two mutations in the CDKN2A (p16) gene were detected, including a novel base change AAC-->ATC (Asn to Ile) at codon 71, that also changes the codon 85 of the alternative reading frame gene p14(ARF) from CAA to CAT (Gln to His). Homozygous deletion at exon 2 of the CDKN2A (INK4-ARF) gene was detected in six cases. In seven cases, the 540C-->G polymorphism in the 3'UTR of the CDKN2A (p16) gene was found in linkage disequilibrium with the 74C-->A polymorphism in intron 1 of the CDKN2B gene (P < 0.0001). These cases had significantly lower expression of the TP53 protein (P = 0.0032). Both 540C-->G and 580C-->T polymorphisms in the 3'UTR of the CDKN2A (p16) gene were associated with significantly shorter progression time from primary to metastatic disease (P = 0.0071). We conclude, that although none of the analyzed cell cycle regulators could be singled out as a major prognostic factor, G(1)/S checkpoint abnormalities remain one of the most significant factors in the development of malignant melanoma.
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PMID:Analysis of G(1)/S checkpoint regulators in metastatic melanoma. 1086 49

The B-cell lymphoproliferative malignancies B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) share characteristics, including overlapping chromosomal aberrations with deletions on chromosome bands 13q14, 11q23, 17p13, and 6q21 and gains on chromosome bands 3q26, 12q13, and 8q24. To elucidate the biochemical processes involved in the pathogenesis of B-CLL and MCL, we analyzed the expression level of a set of genes that play central roles in apoptotic or cell proliferation pathways and of candidate genes from frequently altered genomic regions, namely ATM, BAX, BCL2, CCND1, CCND3, CDK2, CDK4, CDKN1A, CDKN1B, E2F1, ETV5, MYC, RB1, SELL, TFDP2, TNFSF10, and TP53. Performing real-time quantitative reverse transcription polymerase chain reaction in a panel of patients with MCL and B-CLL and control samples, significant overexpression and underexpression was observed for most of these genes. Statistical analysis of the expression data revealed the combination of CCND1 and CDK4 as the best classifier concerning separation of both lymphoma types. Overexpression in these malignancies suggests ETV5 as a new candidate for a pathogenic factor in B-cell lymphomas. Characteristic deregulation of multiple genes analyzed in this study could be combined in a comprehensive picture of 2 distinctive pathomechanisms in B-CLL and MCL. In B-CLL, the expression parameters are in strong favor of protection of the malignant cells from apoptosis but did not provide evidence for promoting cell cycle. In contrast, in MCL the impairment of apoptosis induction seems to play a minor role, whereas most expression data indicate an enhancement of cell proliferation.
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PMID:Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes. 1203 88

Quantitative and structural genetic alterations cause the development and progression of prostate cancer. A number of genes have been implicated in prostate cancer by genetic alterations and functional consequences of the genetic alterations. These include the ELAC2 (HPC2), MSR1, and RNASEL (HPC1) genes that have germline mutations in familial prostate cancer; AR, ATBF1, EPHB2 (ERK), KLF6, mitochondria DNA, p53, PTEN, and RAS that have somatic mutations in sporadic prostate cancer; AR, BRCA1, BRCA2, CHEK2 (RAD53), CYP17, CYP1B1, CYP3A4, GSTM1, GSTP1, GSTT1, PON1, SRD5A2, and VDR that have germline genetic variants associated with either hereditary and/or sporadic prostate cancer; and ANXA7 (ANX7), KLF5, NKX3-1 (NKX3.1), CDKN1B (p27), and MYC that have genomic copy number changes affecting gene function. More genes relevant to prostate cancer remain to be identified in each of these gene groups. For the genes that have been identified, most need additional genetic, functional, and/or biochemical examination. Identification and characterization of these genes will be a key step for improving the detection and treatment of prostate cancer.
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PMID:Prevalent mutations in prostate cancer. 1626 36

DNA methylation in CpG islands is associated with transcriptional silencing. Accurate determination of cytosine methylation status in promoter CpG dinucleotides may provide diagnostic and prognostic value for human cancers. We have developed a quantitative PCR/LDR/Universal Array assay that allows parallel evaluation of methylation status of 75 CpG dinucleotides in the promoter regions of 15 tumor suppressor genes (CDKN2B, CDKN2A, CDKN2D, CDKN1A, CDKN1B, TP53, BRCA1, TIMP3, APC, RASSF1, CDH1, MGMT, DAPK1, GSTP1, and RARB). When compared with an independent pyrosequencing method at a single promoter, the two approaches gave good correlation. In a study using 15 promoter regions and seven blinded tumor cell lines, our technology was capable of distinguishing methylation profiles that identified cancer cell lines derived from the same origins. Preliminary studies using 96 colorectal tumor samples and 73 matched normal tissues indicated CpG methylation is a gene-specific and nonrandom event in colon cancer. This new approach is suitable for clinical applications where sample quantity and purity can be limiting factors.
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PMID:Multiplexed profiling of candidate genes for CpG island methylation status using a flexible PCR/LDR/Universal Array assay. 1636 45

Methionine deprivation stress (MDS) eliminates mitotic activity in melanoma cells regardless of stage, grade, or TP53 status, whereas it has a negligible effect on normal skin fibroblasts. In most cases, apoptosis accounts for the elimination of up to 90% of tumor cells from the culture within 72 hours after MDS, leaving a scattered population of multinucleated resistant cells. Loss of mitosis in tumor cells is associated with marked reduction of cyclin-dependent kinase (CDK) 1 transcription and/or loss of its active form (CDK1-P-Thr(161)), which is coincident with up-regulation of CDKN1A, CDKN1B, and CDKN1C (p21, p27, and p57). Expression of the proapoptotic LITAF, IFNGR, EREG, TNFSF/TNFRSF10 and TNFRSF12, FAS, and RNASEL is primarily up-regulated/induced in cells destined to undergo apoptosis. Loss of Aurora kinase B and BIRC5, which are required for histone H3 phosphorylation, is associated with the accumulation of surviving multinucleated cells. Nevertheless, noncycling survivors of MDS are sensitized to temozolomide, carmustin, and cisplatin to a much greater extent than normal skin fibroblasts possibly because of the suppression of MGMT/TOP1/POLB, MGMT/RAD52/RAD54, and cMET/RADD52, respectively. Sensitivity to these and additional genotoxic agents and radiation may also be acquired due to loss of cMET/OGG1, reduced glutathione reductase levels, and a G(2)-phase block that is a crucial step in the damage response associated with enhancement of drug toxicity. Although the genes controlling mitotic arrest and/or apoptosis in response to low extracellular methionine levels are unknown, it is likely that such control is exerted via the induction/up-regulation of tumor suppressors/growth inhibitor genes, such as TGFB, PTEN, GAS1, EGR3, BTG3, MDA7, and the proteoglycans (LUM, BGN, and DCN), as well as the down-regulation/loss of function of prosurvival genes, such as NFkappaB, MYC, and ERBB2. Although MDS targets several common genes in tumors, mutational variability among melanomas may decide which metabolic and signal transduction pathways will be activated or shutdown.
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PMID:Mitotic arrest, apoptosis, and sensitization to chemotherapy of melanomas by methionine deprivation stress. 1690 95

Downregulation of p27 (cyclin-dependent kinase inhibitor-1B, CDKN1B or KIP1) is caused by increased ubiquitin-mediated proteasomal degradation in colorectal cancer, and has been associated with poor prognosis. CpG island methylator phenotype (CIMP) is a phenotype of colorectal cancer with extensive promoter methylation, and associated with high degree of microsatellite instability (MSI-H) and BRAF mutations. We have recently shown that both CIMP and MSI-H are inversely associated with downregulation of p21 (CDKN1A or CIP1), another cyclin-dependent kinase inhibitor. However, no study to date has examined relationship between p27 and CIMP status in colorectal cancer. Using MethyLight assays, we measured DNA methylation in five CIMP-specific gene promoters {CACNA1G, CDKN2A (p16), CRABP1, MLH1 and NEUROG1} in 706 colorectal cancer samples obtained from two large prospective cohorts. Among the 706 tumors, 112 (16%) were CIMP-high tumors with >or=4/5 methylated promoters. We assessed p27 and p53 expressions by immunohistochemistry. Loss of nuclear p27 expression {observed in 231 tumors (33%)} was significantly associated with CIMP-high, MSI-H and BRAF mutations, and these associations were much more pronounced among p53-negative tumors than p53-positive tumors. When CIMP-high and non-CIMP-high tumors were stratified by MSI status (or KRAS and BRAF status), CIMP-high and MSI-H (but not BRAF mutations) were still significantly associated with nuclear p27 loss. Nuclear p27 loss did not appear to be directly related to CDKN2A (p16) methylation. We conclude that downregulation of nuclear p27 is associated with CIMP-high and MSI-H in colorectal cancer. These associations are stronger among p53 wild-type tumors, implying important interplay of p27 and p53 functions (or dysfunctions) in the development of various molecular subtypes of colorectal cancer.
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PMID:Loss of nuclear p27 (CDKN1B/KIP1) in colorectal cancer is correlated with microsatellite instability and CIMP. 1708 68

Cytoplasmic mislocalization of p27 (CDKN1B/KIP1) is caused by activated AKT1 and has been associated with poor prognosis in various cancers. CIMP in colorectal cancer is characterized by extensive promoter methylation and is associated with MSI-MSI-H and BRAF mutations. We have recently shown a positive correlation between MSI/CIMP and loss of nuclear p27. However, no study has examined cytoplasmic p27 mislocalization in relation to CIMP and MSI in colorectal cancer. Using MethyLight assays, we quantified DNA methylation in 8 CIMP-specific gene promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) in 853 colorectal cancer samples obtained from 2 large prospective cohorts. We assessed expressions of nuclear and cytoplasmic p27 and nuclear p53 by immunohistochemistry. Cytoplasmic p27 expression was inversely associated with loss of nuclear p27 (P < .0001), CIMP-high (P < .0001), MSI-H (P < .0001), and BRAF mutations (P < .0001). The inverse association of cytoplasmic p27 with CIMP-high (or MSI-H) was independent of MSI (or CIMP) status. In addition, the inverse association of cytoplasmic p27 with CIMP-high was independent of KRAS/BRAF status. BRAF and CDKN2A (p16) methylation were not correlated with cytoplasmic p27 after stratification by CIMP status. The inverse associations of cytoplasmic p27 with MSI-H and CIMP-high were much more pronounced in p53-negative than p53-positive tumors. In conclusion, cytoplasmic p27 expression is inversely associated with MSI-H and CIMP-high, particularly in p53-negative tumors, suggesting interplay of functional losses of p27 and p53 in the development of various molecular subtypes of colorectal cancer.
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PMID:Cytoplasmic localization of p27 (cyclin-dependent kinase inhibitor 1B/KIP1) in colorectal cancer: inverse correlations with nuclear p27 loss, microsatellite instability, and CpG island methylator phenotype. 1723 30

We report the molecular characterization of 8 primary gastric carcinomas, corresponding xenografts, and 2 novel gastric carcinoma cell lines. We compared the tumors and cell lines, with respect to histology, immunohistochemistry, copy number, and hypermethylation of up to 38 genes using methylation-specific multiplex ligation-dependent probe amplification, and TP53 and CDH1 mutation analysis where relevant. The primary tumors and xenografts were histologically comparable and shared expression of 11 of 14 immunohistochemical markers (E-cadherin, beta-catenin, COX-2, p53, p16, TFF1, cyclin E, MLH1, SMAD4, p27, KLK3, CASR, CHFR, and DAPK1). Gains of CASR, DAPK1, and KLK3--not yet described in gastric cancer--were present in the primary tumors, xenografts, and cell lines. The most prominent losses occurred at CDKN2A (p16), CDKN2B (p15), CDKN1B (p27/KIP1), and ATM. Except for ATM, these losses were found only in the cell line or xenograft, suggesting an association with tumor progression. However, examination of p16 and p27 in 174 gastric cancers using tissue microarrays revealed no significant correlation with tumor stage or lymph node status. Further losses and hypermethylation were detected for MLH1, CHFR, RASSF1, and ESR, and were also seen in primary tumors. Loss of CHFR expression correlated significantly with the diffuse phenotype. Interestingly, we found the highest rate of methylation in primary tumors which gave rise to cell lines. In addition, both cell lines harbored mutations in CDH1, encoding E-cadherin. Xenografts and gastric cancer cell lines remain an invaluable research tool in the uncovering of the multistep progression of cancer. The frequent gains, losses, and hypermethylation reported in this study indicate that the involved genes or chromosomal regions may be relevant to gastric carcinogenesis.
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PMID:Molecular analysis of primary gastric cancer, corresponding xenografts, and 2 novel gastric carcinoma cell lines reveals novel alterations in gastric carcinogenesis. 1737 10

Damage-induced G1 checkpoint in mammalian cells involves upregulation of p53, which activates transcription of p21(Waf1) (CDKN1A). Inhibition of cyclin-dependent kinase (CDK)2 and CDK4/6 by p21 leads to dephosphorylation and activation of Rb. We now show that ectopic p21 expression in human HT1080 fibrosarcoma cells causes not only dephosphorylation but also depletion of Rb; this effect was p53-independent and susceptible to a proteasome inhibitor. CDK inhibitor p27 (CDKN1B) also caused Rb dephosphorylation and depletion, but another CDK inhibitor p16 (CDKN2A) induced only dephosphorylation but not depletion of Rb. Rb depletion was observed in both HT1080 and HCT116 colon carcinoma cells, where p21 was induced by DNA-damaging agents. Rb depletion after DNA damage did not occur in the absence of p21, and it was reduced when p21 induction was inhibited by p21-targeting short hairpin RNA or by a transdominant inhibitor of p53. These results indicate that p21 both activates Rb through dephosphorylation and inactivates it through degradation, suggesting negative feedback regulation of damage-induced cell-cycle checkpoint arrest.
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PMID:p21(Waf1/Cip1/Sdi1) mediates retinoblastoma protein degradation. 1748 59

Therapies for mantle cell lymphoma (MCL) are clinically unsatisfactory, and the search for effective drugs in vitro might foster the evaluation of their activity in vivo. We have investigated the effects of the polyphenolic compound resveratrol on the MCL cell line Jeko-1 using a combination of flow cytometry, Western blotting and two-dimensional electrophoresis to identify the molecules involved in the induction of apoptosis and cell growth regulation. We show that resveratrol induces apoptosis in Jeko-1 cells and modulates several key molecules, including cyclin D1 (CCND1), p53 (TP53), p21 (CDKN1A), BCL2, BAX, Bcl XL (BCL2L1), caspase 9 (CASP9) and p27 (CDKN1B). By high-resolution 2D-PAGE and nano-reverse phase-high performance liquid chromatography coupled with tandem mass spectrometry, we identified 32 differentially expressed proteins in response to resveratrol treatment that belong to important cell death related networks (including c-myc, NF-kappaB and the mitochondrial apoptotic pathway). These findings may improve the understanding of mechanisms mediating the pro-apoptotic effects of resveratrol on MCL cells, and form the basis for its potential use as a therapeutic agent.
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PMID:Induction of apoptosis in Jeko-1 mantle cell lymphoma cell line by resveratrol: a proteomic analysis. 1850 31


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