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)

The promyelocytic leukemia protein (PML), involved in the pathogenesis of acute promyelocytic leukemia, is a coactivator of p53 tumor suppressive functions. The ability of PML to inhibit growth and induce cell death in solid tumor cells, however, has not been determined. We therefore assayed the tumor suppressor activities of PML and compared them with those of p53 in four liver cancer cell lines. Following infection of cells with replication-deficient recombinant PML adenovirus, the exogenous PML localized in the nucleus and formed abnormally enlarged PML-nuclear bodies after 24 hours. In vitro growth curve analysis showed that the overexpressed PML initially induced a substantial G1 cell cycle arrest and triggered massive cell death in all tested cell lines, irrespective of their p53 status. PML-induced cell death decreased by about 30% in the presence of a broad caspase inhibitor, zVAD. The cell death effect of PML was higher than that induced by p53 over a longer period of time. As with p53, overexpression of PML was closely related to upregulation of p21 and decrease of cyclin D1 expression. Unexpectedly, retinoic acid (RA) antagonized rather than enhanced PML-triggered cell death. RA enhanced the expression of adenovirus-cytomegalovirus-promoted PML at both transcription and protein levels within 12 hours after treatment; however, the PML protein was significantly degraded in the presence of RA at days 3-5 postinfection. PML degradation was also observed in SK-BR3 breast cancer cells treated with RA. Taken together, our findings strongly support the hypothesis that PML acts as a strong independent cell death inducer and that RA conversely abolishes the therapeutic effects of the PML proteins through proteasomal degradation of the protein.
 ...
PMID:Promyelocytic leukemia protein-induced growth suppression and cell death in liver cancer cells. 1552 77

Recent studies have demonstrated that p21WAF1 (now known as CDKN1A)-dependent and -independent accelerated senescence responses are a major determinant of the sensitivity of cancer cells to chemotherapeutic agents. The objective of the present study was to determine whether human solid tumor-derived cell lines that express wild-type TP53 can exhibit levels of CDKN1A induction after exposure to ionizing radiation that are sufficient to activate the accelerated senescence program. Exposure to 60Co gamma radiation (< or =8 Gy) triggered accelerated senescence in all five TP53 wild-type tumor cell lines examined, albeit to differing degrees. Three of the TP53 wild-type tumor cell lines, HCT116, A172 and SKNSH, activated the TP53 signaling pathway similarly to normal human fibroblasts, as judged by the nuclear accumulation of TP53, magnitude and duration of induction of CDKN1A mRNA and CDKN1A protein, and propensity to undergo accelerated senescence after radiation exposure. In the clonogenic survival assay, the degree of radiosensitivity of these three tumor cell lines was also in the range displayed by normal human fibroblasts. On the other hand, two other TP53 wild-type tumor cell lines, A498 and A375, did not maintain high levels of CDKN1A mRNA and CDKN1A protein at late times postirradiation and exhibited only low levels of accelerated senescence after radiation exposure. Studies with a CDKN1A knockout cell line (HCT116CDKN1A-/-) confirmed that the radiation-triggered accelerated senescence is dependent on CDKN1A function. We conclude that (1) clinically achievable doses of ionizing radiation can trigger CDKN1A-dependent accelerated senescence in some human tumor cell lines that express wild-type TP53; and (2) as previously documented for normal human fibroblasts, some TP53 wild-type tumor cell lines (e.g. HCT116, A172 and SKNSH) may lose their clonogenic potential in response to radiation-inflicted injury primarily through undergoing accelerated senescence.
 ...
PMID:Induction of accelerated senescence by gamma radiation in human solid tumor-derived cell lines expressing wild-type TP53. 1560 7

The proteasome is the main extralysosomal system involved in intracellular proteolysis. A number of proteasome substrates, including cyclins, IkappaB, and p53, are critical to cell cycle progression and apoptosis. Interruption of the degradation of these substrates through proteasome inhibition is a novel and unique approach to the treatment of malignancies. First-generation proteasome inhibitors lacked usefulness because of broad specificity and irreversible binding to the proteasome. However, the later synthesis of the peptide boronic acid proteasome inhibitor bortezomib allowed for selective, reversible binding. Basic investigations have reported the antitumor activity of bortezomib in a variety of hematologic and solid tumor models and have demonstrated the ability of bortezomib to enhance chemosensitivity and overcome cellular mechanisms of drug resistance attributable, in part, to abrogation of NF-kappaB induction. In patients with relapsed, refractory multiple myeloma who had received a median of six prior regimens, treatment with bortezomib resulted in a 35% response rate (complete plus partial plus minimal response) using criteria of the European Group for Blood and Marrow Transplantation. Encouraging activity has been demonstrated with bortezomib in the first-line treatment of myeloma and in patients with mantle cell lymphoma. Investigations of its utility in the treatment of patients with solid tumors are ongoing.
 ...
PMID:Proteasome inhibition in the treatment of cancer. 1565 70

Econazole (Eco), a potent broad-spectrum anti-fungal agent, has been used in the treatment of superficial mycosis. Eco is a store-operated Ca2+ channel antagonist which induces cytotoxic cell death of leukemia. However, little is known about its cytotoxic effect upon solid tumor cells. The purpose of this study is to investigate both the in vitro and in vivo molecular mechanisms of Eco-induced toxicity on colon cancer cells. We used COLO 205 cell line and nude mice xenograft model to investigate the cytotoxic effect of Eco. We demonstrated that lower doses Eco (5-20 microM) arrested human colon cancer cells at the G0/G1 phase of the cell cycle. The protein levels of p53, p21/Cip1, and p27/Kip1 were significantly elevated while CDK2 and CDK4 kinase activity were significantly suppressed by Eco treatment in COLO 205 cells. At higher doses (40-60 microM), Eco induced COLO 205 cells apoptosis evidenced by ladder formation in DNA fragmentation assay and sub-G1 peak in flow cytometry analysis. Western blot analysis showed that caspases 3, 9 but not 8 were activated by high dose Eco treatment to the COLO 205 cells accompanied with cytochrome c and apoptosis-inducing factor (AIF) translocation. Significant anti-tumorigenesis effect was further demonstrated in vivo by treating nude mice bearing COLO 205 tumor xenografts with Eco 50 mg/kg intraperitoneally. Our findings highlight the molecular mechanisms underlying the Eco-induced toxicity on colon cancer cells.
 ...
PMID:Molecular mechanisms of econazole-induced toxicity on human colon cancer cells: G0/G1 cell cycle arrest and caspase 8-independent apoptotic signaling pathways. 1591 46

Apoptosis mediated by the proapoptotic BCL-2 family members BCL-2-associated X-protein (BAX) and BCL-2 antagonist/killer (BAK) is part of the antiviral response at the cellular level to limit virus replication. Viruses, in turn, have evolved to encode antiapoptotic BCL-2 homologs (v-BCL-2s) to prevent the premature death of the infected host cell to sustain virus replication. These same v-BCL-2 proteins cooperate with loss of retinoblastoma protein and p53 tumor suppressor function, by inactivating the BAX and BAK apoptotic pathway to promote epithelial solid tumor growth and resistance to chemotherapy. Analogously to infected cells, failure of apoptosis in tumors permits the survival of abnormal, damaged cells displaying chromosome instability that may further promote tumor progression. Thus, both infected cells and tumor cells require inhibition of the apoptotic host defense mechanism, the insights from which can be exploited for therapy development.
 ...
PMID:Mechanisms of apoptosis regulation by viral oncogenes in infection and tumorigenesis. 1667 7

Ganoderma lucidum is a well-known traditional Chinese medicinal herb containing many bioactive compounds. Ganoderic acid T (GA-T), which is a lanostane triterpenoid purified from methanol extract of G. lucidum mycelia, was found to exert cytotoxicity on various human carcinoma cell lines in a dose-dependent manner, while it was less toxic to normal human cell lines. Animal experiments in vivo also showed that GA-T suppressed the growth of human solid tumor in athymic mice. It markedly inhibited the proliferation of a highly metastatic lung cancer cell line (95-D) by apoptosis induction and cell cycle arrest at G(1) phase. Moreover, reduction of mitochondria membrane potential (Delta psi(m)) and release of cytochrome c were observed during the induced apoptosis. Our data further indicate that the expression of proteins p53 and Bax in 95-D cells was increased in a time-dependent manner, whereas the expression of Bcl-2 was not significantly changed; thus the ratio of Bcl-2/Bax was decreased. The results show that the apoptosis induction of GA-T was mediated by mitochondrial dysfunctions. Furthermore, stimulation of the activity of caspase-3 but not caspase-8 was observed during apoptosis. The experiments using inhibitors of caspases (Z-VAD-FMK, Z-DEVD-FMK and Z-IETD-FMK) confirmed that caspase-3 was involved in the apoptosis. All our findings demonstrate that GA-T induced apoptosis of metastatic lung tumor cells through intrinsic pathway related to mitochondrial dysfunction and p53 expression, and it may be a potentially useful chemotherapeutic agent.
 ...
PMID:Ganoderic acid T from Ganoderma lucidum mycelia induces mitochondria mediated apoptosis in lung cancer cells. 1700 87

In order to review gene alterations associated with drug responses in vitro to identify candidate genes for predictive chemosensitivity testing, we selected from literature genes fulfilling at least one of the following criteria for the definition of 'in vitro chemosensitivity associated gene': (i) alterations of the gene can be identified in human solid tumor cell lines exhibiting drug-induced resistance; (ii) transfection of the gene induces drug resistance; (iii) down-regulation of the gene increases the drug sensitivity. We then performed Medline searches for papers on the association between gene alterations of the selected genes and chemosensitivity of cancer cell lines, using the name of the gene as a keyword. A total of 80 genes were identified, which were categorized according to the protein encoded by them as follows: transporters (n = 15), drug targets (n = 8), target-associated proteins (n = 7), intracellular detoxifiers (n = 7), DNA repair proteins (n = 10), DNA damage recognition proteins (n = 2), cell cycle regulators (n = 6), mitogenic and survival signal regulators (n = 7), transcription factors (n = 4), cell adhesion-mediated drug resistance protein (n = 1), and apoptosis regulators (n = 13). The association between the gene alterations and chemosensitivity of cancer cell lines was evaluated in 50 studies for 35 genes. The genes for which the association above was shown in two or more studies were those encoding the major vault protein, thymidylate synthetase, glutathione S-transferase pi, metallothionein, tumor suppressor p53, and bcl-2. We conclude that a total of 80 in vitro chemosensitivity associated genes identified in the literature are potential candidates for clinical predictive chemosensitivity testing.
 ...
PMID:Genes regulating the sensitivity of solid tumor cell lines to cytotoxic agents: a literature review. 1759 44

A 65-year-old woman presented with microscopic hematuria. Computed tomography (CT) and magnetic resonance imaging revealed a solid tumor measuring 64 x 55 x 71 mm adjacent to the right kidney. After 51 days, the CT demonstrated progressive enlargement of the tumor (110 x 80 x 82 mm), and the tumor-doubling time was calculated as 33 days. A transperitoneal right radical nephrectomy was performed. Histologically, the tumor was arising from retroperitoneum and consisted of variable arranged spindle cell proliferation with an infiltration of inflammatory cells. Immunostaining examination showed positive staining for alpha-smooth muscle actin (SMA), vimentin, cytokeatins, and CD 68, whereas desmin, CD 34, and p53 were negative. High proliferative activity (20%) was demonstrated by MIB1 immunostaining. Then the tumor was diagnosed as inflammatory fibrosarcoma. The patient has been followed up for 3 months since the operation with no evidence of local recurrence or distant metastasis.
 ...
PMID:[A case report: retroperitoneal inflammatory fibrosarcoma that revealed progressive enlargement]. 1762 37

For pediatric cancers like neuroblastoma, the most common extracranial solid tumor of infancy, p53 mutations are rare at diagnosis, but may be acquired after chemotherapy, suggesting a potential role in drug resistance. Heavy metal-selected neuroblastoma cells were found to acquire an unusually broad multidrug resistance (MDR) phenotype but displayed no alterations in genes associated with "classic" MDR. These cells had acquired a mutant p53 gene, linking p53 to drug sensitivity in neuroblastoma. We therefore generated p53-deficient variants in neuroblastoma cell lines with wild-type p53 by transduction of p53-suppressive constructs encoding either short hairpin RNA or a dominant-negative p53 mutant. Analysis of these cells indicated that (a) in contrast to previous reports, wild-type p53 was fully functional in all neuroblastoma lines tested; (b) inactivation of p53 in neuroblastoma cells resulted in establishment of a MDR phenotype; (c) p53-dependent senescence, the primary response of some neuroblastoma cells to DNA damage, is replaced after p53 inactivation by mitotic catastrophe and subsequent apoptosis; (d) knockdown of mutant p53 did not revert the MDR phenotype, suggesting it is determined by p53 inactivation rather than gain of mutant function. These results suggest the importance of p53 status as a prognostic marker of treatment response in neuroblastoma. p53 suppression may have opposite effects on drug sensitivity as determined by analysis of isogenic pairs of tumor cell lines of nonneuroblastoma origin, indicating the importance of tissue context for p53-mediated modulation of tumor cell sensitivity to treatment.
 ...
PMID:p53 determines multidrug sensitivity of childhood neuroblastoma. 1797 78

Neuroblastoma (NB) is the most common malignant solid tumor in childhood. There are well-recognized prognostic factors in NB such as age at diagnosis, organ of origin, stages, MYCN gene amplification, and expression of H-ras, trkA and survivin. Moreover, we investigated the expression of vascular endothelial growth factor (VEGF), tyrosine hydroxylase (TH), p53, stem cell factor (SCF) and c-kit of its receptor with quantitative real-time polymerase chain reaction (PCR) in 22 NBs and 4 other tumors (one malignant lymphoma, one malignant teratoma, and 2 rhabdomyosarcomas) samples. The correlation between patients' prognoses and the expression of TH or c-kit was newly recognized, particularly the good prognosis in patients in whom c-kit highly expressed and the poor prognosis contrarily associated with low or no expression, although the SCF of its ligand had no relationship with patient prognosis. It is possible that tumors without c-kit expression can not react with SCF (via the autocrine or paracrine system) and remain immature. It may be that this is a new critical clinical event in NB patients.
 ...
PMID:Analyses of novel prognostic factors in neuroblastoma patients. 1805 15


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>