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)

The present study was carried out in order to examine the molecular status of selected growth factor receptors (GFR) in urinary bladder lesions, recently described by our group as representing 'Chernobyl cystitis'. Fibroblast growth factor receptor 3 (FGFR3), epidermal growth factor receptor 1 (EGFR1), EGFR2neu (a member of the same family), p53 and Raf-1 serine/threonine kinase expression were evaluated immunohistochemically in urinary bladder biopsies from 22 men with benign prostate hyperplasia (group 1). For comparison, 16 men with benign prostate hyperplasia and five women with chronic cystitis living in non-radio-contaminated areas of the country were also investigated as controls (group 2). Additionally, 14 patients with dysplasia, carcinoma in situ (CIS) and primary urothelial carcinoma (UC) operated before the Chernobyl accident as well as 23 patients with UC living in the radio-contaminated areas were included as pre- and post-Chernobyl UC groups 1 and 2, respectively. Chronic proliferative atypical cystitis ('Chernobyl cystitis') was observed in group 1 patients. Foci of dysplasia and CIS were found in 22 (100%) and 19 (86%) of the 22 cases, respectively; moreover, two small UC were also detected. Elevated levels of FGFR3, EGFR2/neu, p53 and to a lesser extent EGFR1 and Raf-1 expression in the urothelial dysplasia and CIS were evident for patients of group 1. Statistically significant differences in immunohistochemical scores for FGFR3, EGFR1, p53 and Raf-1 were observed between groups 1 and 2 and between group 1 and the post-Chernobyl UC group 2, where a change in expression of EGFR2/neu was also noted. A significant decrease in FGFR3 expression in additional pre-Chernobyl UC group 1 with dysplasia, CIS and UC compared with group 1 Chernobyl cystitis cases was detected. Our findings suggest that FGFR and EGFR signaling pathways, associated with p53 and Raf-1 activation, may contribute to multistage urothelial carcinogenesis caused by irradiation, through autocrine or paracrine growth stimulation.
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PMID:Upregulation of fibroblast growth factor receptor 3 and epidermal growth factor receptors, in association with Raf-1, in urothelial dysplasia and carcinoma in situ after the Chernobyl accident. 1696 95

Development of new molecular target therapeutic agents is expected to improve clinical outcome, ideally with efficacy in both single and combined treatment modalities. Because of the potential for affecting multiple signaling pathways, inhibition of the molecular chaperone heat shock protein 90 (Hsp90) may provide a strategy for enhancing tumor cell radiation sensitivity. Therefore, we have investigated the effects of Hsp90 inhibitor 17-Allylamino-17-demethoxygeldanamycin (17-AAG) on radiation sensitivity of human tumor cells in vitro. We evaluated the effects of 17-AAG using oral squamous cell carcinoma (OSCC) cell lines (HSC2, HSC3 and HSC4), including two types of SAS cells with a wild-type (SAS/neo), or a mutated p53 status (SAS/Trp248). Apoptosis and clonogenic survival were examined after exposure of the cells to radiation. For mechanistic insight, we analyzed cell cycle, several signaling factors and molecular markers including Akt, Raf-1, p38 MAPK, Cdc25B, Cdc25C, Cdk2 and p21. Treatment of OSCC cell lines with 17-AAG resulted in cytotoxicity and, when combined with radiation, enhanced the radiation response. However, the responses depended on p53 status. 17-AAG enhanced the radiation sensitivity significantly and induced apoptosis in the SAS/neo cell which has a wild-type p53. But the radiation sensitizing effect of 17-AAG was limited in the SAS/Trp248 cell which has a mutated p53. We also measured the total levels of several prosurvival and cell cycle signaling proteins. Akt, Raf-1 and Cdc25C expression were down-regulated in 17-AAG-treated cells. These data indicate that 17-AAG inhibits the proliferation and enhances the radiation sensitivity of human OSCC cells in various levels. However, enhancement of radiation sensitivity by the Hsp90 inhibitor depended on p53 status. Therefore, Hsp90 therapy combined with radiation might synergize with conventional therapies in patients with wild-type p53.
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PMID:P53-dependent radiosensitizing effects of Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin on human oral squamous cell carcinoma cell lines. 1701 41

The role of various inflammatory mechanisms and oxidative stress in the development of atherosclerosis and arterial hypertension (AH) has been increasingly acknowledged during recent years. Hypertension per se or factors that cause hypertension along with other complications lead to infiltration of activated leukocytes in the vascular wall, where these cells contribute to the development of vascular injury by releasing cytokines, oxygen radicals, and other toxic mediators. However, molecular mechanisms underlying leukocyte activation at transcriptional level in AH are still far from being clear. To solve this problem we employed cDNA microarray technology to reveal the differences in gene expression in peripheral blood leukocytes from patients with AH compared with healthy individuals. The microarray data were verified by a semi-quantitative RT-PCR method. We found 25 genes with differential expression in leukocytes from AH patients among which 21 genes were upregulated and 4 genes were downregulated. These genes are implicated in apoptosis (CASP2, CASP4, and CASP8, p53, UBID4, NAT1, and Fte-1), inflammatory response (CAGC, CXCR4, and CX3CR1), control of MAP kinase function (PYST1, PAC1, RAF1, and RAFB1), vesicular trafficking of molecules among cellular organelles (GDI-1 and GDI-2), cell redox homeostasis (GLRX), cellular stress (HSPA8 and HSP40), and other processes. Gene expression pattern of the majority of genes was similar in AH patients independent of the disease stage and used hypotensive therapy, but was clearly different from that of normotensive subjects.
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PMID:Altered gene expression pattern in peripheral blood leukocytes from patients with arterial hypertension. 1734 25

Epidemiological data suggest that epigallocatechin-3-gallate (EGCG) possesses chemopreventive properties against cancer. In this study, we examined the molecular mechanisms of EGCG in human pancreatic cancer cells. EGCG caused growth arrest at G1 stage of cell cycle through regulation of cyclin D1, cdk4, cdk6, p21/WAF1/CIP1 and p27/KIP1, and induced apoptosis through generation of reactive oxygen species and activation of caspase-3 and caspase-9. EGCG inhibited expressions of Bcl-2 and Bcl-XL and induced expressions of Bax, Bak, Bcl-XS and PUMA. Mouse embryonic fibroblasts (MEFs) derived from Bax and Bak double knockout mice exhibited greater protection against EGCG-induced apoptosis than wild-type or single knockout MEFs. EGCG caused Bax activation in p53 -/- MEFs, suggesting that EGCG can induce apoptosis in the absence of p53. Furthermore, the activities of Ras, Raf-1 and ERK1/2 were inhibited, whereas the activities of MEKK1, JNK1/2 and p38 MAP kinases were induced by EGCG. Inhibition of cRaf-1 or ERK enhanced EGCG-induced apoptosis, whereas inhibition of JNK or p38 MAP kinase inhibited EGCG-induced apoptosis. EGCG inhibited the activation of p90 ribosomal protein S6 kinase, and induced the activation of cJUN. Our results suggest that EGCG induces growth arrest and apoptosis through multiple mechanisms, and can be used for pancreatic cancer prevention.
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PMID:Epigallocatechin-3-gallate inhibits cell cycle and induces apoptosis in pancreatic cancer. 1756 28

Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for the stability and function of multiple mutated, chimeric and over-expressed signaling proteins that promote the growth and/or survival of cancer cells. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2) and HIF-1alpha. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and the first-in-class Hsp90 inhibitor, 17-allylamino-17 demethoxygeldanamycin (17AAG), is currently in phase II clinical trials. A fraction of Hsp90 has been identified at the cell surface and its presence has recently been shown to correlate with melanoma progression. Inhibition of cell-surface Hsp90 with antibodies or cell-impermeable Hsp90 inhibitors blocks cell motility and invasion in vitro and cancer metastasis in vivo. Thus, cell-surface Hsp90 may play a unique role in tumor metastasis, distinct from but perhaps overlapping with its intracellular function. In addition, because cell-surface Hsp90 may be the point of contact between some viruses and host cells, this pool of the chaperone may play a distinct role in initiation of infectious disease.
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PMID:Extracellular heat shock protein 90: a role for a molecular chaperone in cell motility and cancer metastasis. 1764 79

We used microarray-based comparative genomic hybridization to explore genome-wide profiles of chromosomal aberrations in 26 samples of head and neck cancers compared to their pair-wise normal controls. The samples were obtained from Sudanese (n=11) and Norwegian (n=15) patients. The findings were correlated with clinicopathological variables. We identified the amplification of 41 common chromosomal regions (harboring 149 candidate genes) and the deletion of 22 (28 candidate genes). Predominant chromosomal alterations that were observed included high-level amplification at 1q21 (harboring the S100A gene family) and 11q22 (including several MMP family members). Regions of copy number increase was also identified at 6p21 (p21), 7p12 (EGFR), 17p13 (p53) and 19p13.2 (p19INK4d), while regions showing deletion included among others 3p25.2 (RAF1) and 9p21 (p15, p16). We found genes from four common biological pathways (MAPK signaling, cytokine-cytokine receptor interaction, ECM-receptor interaction and Jak-STAT signaling) to be predominantly over-represented in areas of gain and loss. The current study provides valuable information on chromosomal aberrations likely to be involved in the pathogenesis of head and neck cancers. An increased copy number of the S100A and MMP gene family members, known to be involved in invasion and metastasis, may play an important role in the development of the tumors. Hierarchical clustering of the chromosomal alterations with clinicopathological parameters showed little correlation, suggesting an occurrence of gains/losses regardless of ethnic differences and clinicopathological status between the patients from the two countries. Our findings indicate the existence of common gene-specific amplifications/deletions in these tumors, regardless of the source of the samples or attributed carcinogenic risk factors.
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PMID:Chromosomal aberrations in head and neck squamous cell carcinomas in Norwegian and Sudanese populations by array comparative genomic hybridization. 1881 24

The heat shock protein Hsp72 is expressed at the elevated levels in various human tumors, and its levels often correlate with poor prognosis. Previously we reported that knockdown of Hsp72 in certain cancer cells, but not in untransformed breast epithelial cells, triggers senescence via p53-dependent and p53-independent mechanisms. Here we demonstrate that the p53-dependent pathway controlled by Hsp72 depends on the oncogenic form of phosphatidylinositol 3-kinase (PI3K). Indeed, upon expression of the oncogenic PI3K, epithelial cells began responding to Hsp72 depletion by activating the p53 pathway. Moreover, in cancer cell lines, activation of the p53 pathway caused by depletion of Hsp72 was dependent on oncogenes that activate the PI3K pathway. On the other hand, the p53-independent senescence pathway controlled by Hsp72 was associated with the Ras oncogene. In this pathway, extracellular signal-regulated kinases (ERKs) were critical for senescence, and Hsp72 controlled the ERK-activating kinase cascade at the level of Raf-1. Importantly, upon Ras expression, untransformed cells started responding to knockdown of Hsp72 by constitutive activation of ERKs, culminating in senescence. Therefore, Hsp72 is intimately involved in suppression of at least two separate senescence signaling pathways that are regulated by distinct oncogenes in transformed cells, which explains why cancer cells become "addicted" to this heat shock protein.
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PMID:Heat shock protein Hsp72 controls oncogene-induced senescence pathways in cancer cells. 1900 Oct 88

The infection with Friend murine leukemia virus (FMuLv) is being used as a retrovirus infection model for searching the potential anti-viral medicinal preparations or establishing new treatment strategies. In the present study we have evaluated the inhibitory effect of three non-toxic antiviral natural compounds namely berberine, curcumin or picroliv against FMuLv induced erythroleukemia in BALB/c mice. To understand the effect of these compounds in the initiation and progression of leukemia we did a series of analysis, which include hematological and biochemical parameters, histopathological evaluations of the liver and the spleen and expression analysis of selected genes such as Bcl-2, p53, p45NFE2, Raf-1, Erk-1, IFNgamma receptor and erythropoietin in spleen. The treatment with berberine, curcumin or picroliv were found to (a) elevate the life span of leukemia harboring animals by more than 60 days; (b) decreased the anemic condition which was highly prevalent in FMuLv alone treated group; (c) histopathological evaluations showed that the compounds tested here inhibited the massive leukemic cell infiltrations to sinusoidal spaces in spleen; (d) decrease the expression of Bcl-2, Raf-1, Erk-1 IFNgamma receptor and erythropoietin; (e) induce the expression of p53. Overall, our results suggest that berberine, curcumin and picroliv were able to suppress the progression of leukemia induced by FMuLv and further support their chemopreventive potential against virally induced cancers.
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PMID:Inhibition of progression of erythroleukemia induced by Friend virus in BALB/c mice by natural products--berberine, curcumin and picroliv. 1922 7

The extracellular signal-regulated (ERK), mitogen-activated protein kinase (p42/p44 MAPK) pathway is up-regulated in hepatocellular carcinoma (HCC). Molecular targeting of this critical mitogenic pathway may have therapeutic potential for the treatment of HCC; however, chemoresistance to long-term therapy may develop. In the present study, we employed small-molecule MAPK kinase (MEK) inhibitors, including U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene] and PD184161 (Neoplasia 8:1-8, 2006), in HepG2 and Hep3B human HCC cell lines to identify potential mechanism(s) of resistance. U0126 dose-dependently suppressed ERK phosphorylation at both 1- and 24-h time points in HepG2 cells, previously shown to be sensitive to growth inhibition by U0126. In contrast, ERK phosphorylation was only decreased at the 1-h time point but not at 24 h in the more resistant Hep3B cells. It is interesting that the lack of prolonged phospho-ERK suppression was associated with MEK hyperphosphorylation in Hep3B cells. Several MEK/ERK pathway intermediates were up-regulated in Hep3B cells; furthermore, transfection of Raf-1 small interfering RNA to suppress MEK/ERK pathway activation sensitized Hep3B cells to U0126. MEK inhibitor resistance was independent of p53 or hepatitis Bx protein status. Finally, we showed that combining two chemically distinct MEK inhibitors enhanced growth inhibition and apoptosis compared with the single agents. Taken together, these results suggest that up-regulated expression or activity of the MEK/ERK pathway contributes to MEK inhibitor resistance in HCC cells. Our findings also provide preclinical evidence suggesting that the status of the MEK/ERK pathway in patients may predict response to MEK/ERK-targeted therapeutics.
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PMID:Resistance to mitogen-activated protein kinase kinase (MEK) inhibitors correlates with up-regulation of the MEK/extracellular signal-regulated kinase pathway in hepatocellular carcinoma cells. 1925 20

Wilms tumor is one of the most common solid tumors in children. We evaluated expression and amplification of a number of genes and their prognostic significance in 45 patients with Wilms tumor, using tissue microarray technology. The expression of EGFR, ERBB2, MDM2, CCND1, MLH1, MSH2, TP53, and ABCB1 (alias MDR1) was studied by immunohistochemistry. Amplification of the EGFR, ERBB2, MDM2, CCND1, CTTN (previously EMS1), RAF1, MYC, FGF3 (previously INT2), WNT1, GLI1, CDK4, and NCOA3 (alias AIB1) genes was assessed by fluorescence in situ hybridization. Expression of EGFR was seen in 17 of the 45 cases (38%) but was not associated with gene amplification. The ERBB2 gene was neither overexpressed nor amplified in any case. Tissue microarray and immunohistochemistry analyses for ERBB2 in whole-tumor sections were also negative in all cases. Strong p53 reactivity was noted in blastemal cells in two cases with an unfavorable outcome. ABCB1 reactivity was seen in five cases with favorable histology and outcome. Only one case showed nuclear cyclin D1 positivity. All tumors showed MLH1 and MSH2 expression. All examined genes showed normal copy numbers. Unfavorable histology correlated with poor prognosis (P=0.03). There was no significant association between gene expression and prognosis. Overexpression of the EGFR gene in many Wilms tumor cases warrants further study to determine the therapeutic benefit of EGFR inhibitors in combination with other therapies in Wilms tumor patients.
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PMID:Amplification and expression of EGFR and ERBB2 in Wilms tumor. 1978 41


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