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)

Histone deacetylase inhibitors (HDACIs) are a class of antineoplastic agents previously demonstrating preclinical chemosensitizing activity against drug-resistant cancer cells and mouse xenografts. However, whereas clinical studies have shown efficacy against human hematologic malignancies, solid tumor trials have proved disappointing. We previously developed a novel HDACI, "OSU-HDAC42," and herein examine its activity against ovarian cancer cell lines and xenografts. OSU-HDAC42, (i) unlike most HDACIs, elicited a more than five-fold increase in G(2)-phase cells, at 2.5 microM, with G(2) arrest followed by apoptosis; (ii) at 1.0 microM, completely repressed messenger RNA expression of the cell cycle progression gene cdc2; (iii) at low doses (0.25-1.0 microM for 24 hours), induced tumor cell epithelial differentiation, as evidenced by morphology changes and a more than five-fold up-regulation of epithelium-specific cytokeratins; (iv) potently abrogated the growth of numerous ovarian cancer cells, with IC(50) values of 0.5 to 1.0 microM, whereas also remaining eight-fold less toxic (IC(50) of 8.6 microM) to normal ovarian surface epithelial cells; and (v) chemosensitizated platinum-resistant mouse xenografts to cisplatin. Compared with the clinically approved HDACI suberoylanilide hydroxamic acid (vorinostat), 1.0 microM OSU-HDAC42 was more biochemically potent (i.e., enzyme-inhibitory), as suggested by greater gene up-regulation and acetylation of both histone and nonhistone proteins. In p53-dysfunctional cells, however, OSU-HDAC42 was two- to eight-fold less inductive of p53-regulated genes, whereas also having a two-fold higher IC(50) than p53-functional cells, demonstrating some interaction with p53 tumor-suppressive cascades. These findings establish OSU-HDAC42 as a promising therapeutic agent for drug-resistant ovarian cancer and justify its further investigation.
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PMID:A rationally designed histone deacetylase inhibitor with distinct antitumor activity against ovarian cancer. 1948 44

Arsenic trioxide has been used as a therapeutic agent for acute promyelocytic leukemia and recently for some solid tumors. Although arsenic trioxide has been shown to significantly inhibit the growth of solid tumor cells in vitro, clinical trials indicate that arsenic trioxide alone is pool active against non-hematologic malignant diseases. To understand the mechanisms of arsenic resistance in solid tumor cells, we established two arsenic-resistant solid tumor cell lines, HepG2/AS and SGC7901/AS, isolated from human liver cancer cell line HepG2 and human gastric cancer cell line SGC7901, respectively, by a series of stepwise selections via treatment with increasing concentrations of arsenic trioxide. Three ABC transporter proteins, ABCB1, ABCC1 and ABCC2, were expressed increasingly and differently in two arsenic-resistant cell lines. Further, tumor suppressor p53 was overexpressed in two arsenic-resistant cell lines, but the levels of p53 mediators MDM2 and gankyrin, which regulate the ubiquitination of p53, increased simultaneously. In addition, an increase in the phosphorylation of Rb at Ser795 in the two cell lines might also result from the presence of MDM2 and gankyrin, which suggest that the inactivation of p53 and Rb contribute to drug resistance. These two arsenic-resistant solid tumor cell lines, HepG2/AS and SGC7901/AS, may be useful for studying the mechanism of arsenic resistance in solid tumors and may provide a way to overcome it.
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PMID:The overexpression of multidrug resistance-associated proteins and gankyrin contribute to arsenic trioxide resistance in liver and gastric cancer cells. 1951 7

Antiangiogenic effects of the proteasome inhibitor bortezomib were analyzed on tumor xenografts in vivo. Bortezomib strongly inhibited angiogenesis and vascularization in the chicken chorioallantoic membrane. Bortezomib's inhibitory effects on chorioallantoic membrane vascularization were abrogated in the presence of distinct tumor xenografts, thanks to a soluble factor secreted by tumor cells. Through size-exclusion and ion-exchange chromatography as well as mass spectroscopy, we identified GRP-78, a chaperone protein of the unfolded protein response, as being responsible for bortezomib resistance. Indeed, a variety of bortezomib-resistant solid tumor cell lines (PC-3, HRT-18), but not myeloma cell lines (U266, OPM-2), were able to secrete high amounts of GRP-78. Recombinant GRP-78 conferred bortezomib resistance to endothelial cells and OPM-2 myeloma cells. Knockdown of GRP78 gene expression in tumor cells and immunodepletion of GRP-78 protein from tumor cell supernatants restored bortezomib sensitivity. GRP-78 did not bind or complex bortezomib but induced prosurvival signals by phosphorylation of extracellular signal-related kinase and inhibited p53-mediated expression of proapoptotic Bok and Noxa proteins in endothelial cells. From our data, we conclude that distinct solid tumor cells are able to secrete GRP-78 into the tumor microenvironment, thus demonstrating a hitherto unknown mechanism of resistance to bortezomib.
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PMID:GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib. 1971 65

Such biological parameters as tumor volume, Ki-67 and p53, which characterize the development of ascites and solid tumor of Ehrlich were evaluated. The kinetic curve of growth of ascites tumor was S-shaped (Gomperts) while that of the solid one--cubic (Speer-Retsky). Ki-67 expression level was found to be in cyclic correlation with duration (3 and 6 day intervals) which might be worth considering when working out therapeutic procedure. Moreover, no increase in cell death was observed when tumor growth slowed down.
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PMID:[Kinetic features of ascites and solid Ehrlich tumors]. 2002 Jun 56

Malignant astrocytomas are a deadly solid tumor in children. Limited understanding of their underlying genetic basis has contributed to modest progress in developing more effective therapies. In an effort to identify such alterations, we performed a genome-wide search for DNA copy number aberrations (CNA) in a panel of 33 tumors encompassing grade 1 through grade 4 tumors. Genomic amplifications of 10-fold or greater were restricted to grade 3 and 4 astrocytomas and included the MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13), and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26), and TP53 (17p3.1) were evident among grade 2 to 4 tumors. BRAF gene rearrangements that were indicated in three tumors prompted the discovery of KIAA1549-BRAF fusion transcripts expressed in 10 of 10 grade 1 astrocytomas and in none of the grade 2 to 4 tumors. In contrast, an oncogenic missense BRAF mutation (BRAF(V600E)) was detected in 7 of 31 grade 2 to 4 tumors but in none of the grade 1 tumors. BRAF(V600E) mutation seems to define a subset of malignant astrocytomas in children, in which there is frequent concomitant homozygous deletion of CDKN2A (five of seven cases). Taken together, these findings highlight BRAF as a frequent mutation target in pediatric astrocytomas, with distinct types of BRAF alteration occurring in grade 1 versus grade 2 to 4 tumors.
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PMID:Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. 2006 83

Myc proteins (c-myc, Mycn and Mycl) target proliferative and apoptotic pathways vital for progression in cancer. Amplification of the MYCN gene has emerged as one of the clearest indicators of aggressive and chemotherapy-refractory disease in children with neuroblastoma, the most common extracranial solid tumor of childhood. Phosphorylation and ubiquitin-mediated modulation of Myc protein influence stability and represent potential targets for therapeutic intervention. Phosphorylation of Myc proteins is controlled in-part by the receptor tyrosine kinase/phosphatidylinositol 3-kinase/Akt/mTOR signaling, with additional contributions from Aurora A kinase. Myc proteins regulate apoptosis in part through interactions with the p53/Mdm2/Arf signaling pathway. Mutation in p53 is commonly observed in patients with relapsed neuroblastoma, contributing to both biology and therapeutic resistance. This review examines Myc function and regulation in neuroblastoma, and discusses emerging therapies that target Mycn.
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PMID:Myc proteins as therapeutic targets. 2010 Dec 14

The author herein reports histopathologic features of 31 surgical cases of gastrointestinal stromal tumor (GIST) of the digestive organs. The 31 cases of GIST were diagnosed in our pathology laboratory. They consisted of 24 cases of gastric GIST, 1 case of hepatic GIST, 1 case of small intestinal GIST, 4 cases of colon GIST, and 1 case of rectal GIST. The age of the patients ranged from 56 year to 84 years with a mean of 71 years. Male to female ratio was 21:10. The presenting symptoms were gastrointestinal bleeding in 13 cases, abdominal pain and discomfort in 13 cases, and asymptomatic in 5 cases. Endoscopy and imaging modalities including US, CT and MRI were useful to detect the tumors in all cases, and biopsies confirmed the GIST diagnosis in 21 cases. The size of GIST ranged from 1 cm to 12 cm with a mean of 4.3 cm. Grossly, 23 cases were submucosal tumors, 6 serosa-side tumors, 1 solid tumor in the liver, and 1 rectal polyp. Histologically, 28 cases were of spindle cell type and 3 of epithelioid type. According to mitotic counts and tumor size, the malignant risk was very low in 4 cases, low in 14 cases, intermediate in 9 cases, and high in 4 cases. Immunohistochemically, all cases were positive for KIT and vimentin, 30 cases for CD34, and 4 cases for alpha-smooth muscle actin. None were positive for desmin and S100 protein. Ki-67 labeling ranged from 2% to 18%. P53 protein was negative in all cases. PDGFRA was positive in 20 cases among 24 cases examined. Genetic analysis using PCR-direct sequencing method was performed in 5 GISTs; all the 5 GISTs showed point mutations or deletions in KIT gene, but did not in PDGFRA gene. The 5 cases of GIST were positive for PDGFRA protein, suggesting that PDGFRA overexpression is not associated with PDGFRA gene mutations. Four of the 31 cases showed metastases. The chemotherapy was imatinib mesylate in 6 cases, and none in 25 cases. Four cases of high risk died of GIST, and 27 cases are alive now without tumors.
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PMID:Gastrointestinal stromal tumor of the digestive organs: a histopathologic study of 31 cases in a single Japanese institute. 2012 84

Angiocentric gliomas (AG) have only recently been described. We encountered a 25-year-old woman with AG who had a history of epilepsy for two years. MRI revealed that there was a solid tumor in the hippocampus. The tumor was totally removed. Histologically, the spindle tumor cells proliferated around small parenchymal vessels with perivascular pseudorosettes. The tumor cells of the hippocampus surface umbilicated forming rosettes. Immunohistochemistry demonstrated positivity for GFAP, Vimentin and S-100, but were negative for neurofilament protein, Syn, CgA and P53. EMA had "dot-like" positive staining. The proliferation index was less than 1%. The location of the tumor and the pathological findings confirm that the diagnose was AG. Epilepsy disappeared after the operation. When fully resected these tumors have a good prognosis.
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PMID:A 25-year-old woman with a mass in the hippocampus. 2043 70

The current WHO classification of brain tumors defines gliomatosis cerebri (GC) as an extensively infiltrating astrocytic glioma involving at least three cerebral lobes. The relation of GC to diffuse astrocytomas and glioblastoma is uncertain. Due to malignant biological behavior, GC is allotted to WHO grade III. Recent reports showed IDH1 mutations in astrocytic and oligodendroglial tumors WHO grades II and III and in secondary glioblastomas with a frequency of up to 90%, whereas IDH1 mutations occurred in only 5% of primary glioblastomas. Here, we examined the frequency of IDH1 mutations in 35 GC samples by direct sequencing, derived cleaved amplified polymorphic sequence analysis and immunohistochemistry. We identified IDH1 mutations in 10/24 (42%) cases, which also included a solid tumor portion (type 2 GC), but not in 11 "classical" cases without solid tumor mass (type 1 GC). TP53 mutations were revealed in two type 2 GC, but not in any type 1 GC, while combined chromosomal losses of 1p and 19q were not found at all. Our data suggest that GC consists of two histological/molecular subtypes, type 1 being clearly distinct from diffuse astrocytoma, and type 2 sharing features with diffuse astrocytoma.
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PMID:Detection of IDH1 mutations in gliomatosis cerebri, but only in tumors with additional solid component: evidence for molecular subtypes. 2053 95

Ameloblastoma is the most frequently encountered odontogenic tumor, characterized by a locally invasive behavior, frequent recurrences, and, although rare, metastatic capacity. Loss or inactivation of tumor suppressor genes (TSGs) allows cells to acquire neoplastic growth. The ING family proteins are tumor suppressors that physically and functionally interact with p53 to perform important roles in apoptosis, DNA repair, cell cycle regulation, and senescence. TP53 genetic alterations were reported to infrequently occur in ameloblastoma. Considering that other TSGs related to TP53 could be altered in this tumor, we focused our study on the ING family genes. We analyzed the loss of heterozygosity (LOH) status of the ING family (ING1-ING5) chromosomal loci in a group of ameloblastomas by microsatellite analysis, and correlated the ING LOH status with clinicopathological characteristics. By using specific microsatellite markers, high frequency of LOH was found at the loci of each ING gene family member (33.3-72.2%). A significant relationship was shown between LOH of D2S 140 (ING5 locus) and solid tumor type (p = 0.02). LOH of ING3MS (ING3 locus) was also high in solid type tumors, showing a near significant association. In addition, a notable tendency toward higher LOH for half of the markers was observed in recurrent cases. LOH of ING family genes appears as a common genetic alteration in solid ameloblastoma. The current study provides interesting novel information regarding the potential prognostic significance of the allelic loss of the ING gene family loci in ameloblastoma tumorigenesis.
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PMID:Allelic loss of the ING gene family loci is a frequent event in ameloblastoma. 2068 10


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