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)

Squamous cell carcinomas of the head and neck (HNSCCs) are characterized by a high frequency of mutations in the p53 gene often leading to p53 protein accumulation. Since accumulation of p53 is associated with enhanced presentation of wild-type sequence (wt) p53 peptides to immune cells, the development of ' pan' vaccines against HNSCC has focused on wt p53 epitopes. We used the HLA-A2.1-restricted wt p53 264-272 epitope pulsed on autologous dendritic cells to generate cytotoxic T lymphocytes (CTLs) ex vivo from circulating precursor T cells of HLA-A2.1+ patients with HNSCC. CTLs specific for the wt p53 264-272 peptide were generated from leukocytes obtained from a cohort of patients with HNSCC (group A). Paradoxically, none of those patients had tumors which adequately presented the epitope, i.e. accumulated p53. In contrast, patients who did not generate CTLs (group B) had tumors which accumulated altered p53 and potentially could present the p53 264-272 epitope. When p53 264-272-specific T cells were directly enumerated in the peripheral circulation of patients with HNSCC using tetrameric p53 264-272/HLA-A2.1 complexes by multicolor flow cytometry, group A had high and group B low percentages of tetramer+ CD3+ CD8+ T cells. These findings suggested that in vivo p53-specific CTLs in group A might play a role in the elimination of tumor cells expressing the p53 264-272 epitope ('immunoselection'), leading to the outgrowth of 'epitope loss' tumor cells. On the other hand, precursor CTLs specific for the wt p53 264-272 peptide in group B are unresponsive to the p53 antigen. Unresponsiveness of CTLs specific for the wt p53264-272 peptide detected in group B could be reversed by using more immunogenic variant peptides of the p53 264-272 epitope. In vivo, immunoselection of tumors which become resistant to anti-p53 immune responses has important implications for future p53-based vaccination strategies. It calls for modified approaches, in which altered peptide variants of the wt sequence p53 264-272 epitope are used in a vaccine in order to overcome unresponsiveness of T lymphocytes to the native epitope.
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PMID:p53 as an immunotherapeutic target in head and neck cancer. 1560 25

p33ING1b can stimulate cell cycle arrest, DNA repair, apoptosis and chemosensitivity. The actions of p33ING1b involve p53-dependent and p53-independent mechanisms. To investigate if the p33ING1b isoform is involved in the chemosensitivity of osteosarcoma cells, p33ING1b was overexpressed in p53+/+ U2OS cells or p53-mutant MG63 cells, and then cell growth arrest and apoptosis were assessed after treatment with taxol. The results showed that p33ING1b markedly increased taxol-induced growth inhibition and apoptosis in p53+/+ U2OS cells, but not in p53-mutant MG63 cells. Moreover, ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. p33ING1b may be an important marker and/or therapeutic target in the prevention and treatment of osteosarcoma.
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PMID:The tumor suppressor p33ING1b enhances taxol-induced apoptosis by p53-dependent pathway in human osteosarcoma U2OS cells. 1571 Nov 22

The roles of p33ING2 as a tumor suppressor candidate have been shown through regulation of gene transcription, induction of cell cycle arrest, and apoptosis. As p33ING2 shares 58.9% homology with p33ING1b, we hypothesized that p33ING2 shares functional similarities with p33ING1b. We previously found that p33ING1b cooperates with p53 to enhance UVB-induced apoptosis. Here, we report that overexpression of p33ING2 enhanced apoptosis in UVB-irradiated and non-irradiated melanoma MMRU cells. We demonstrate that enhancement of apoptosis by p33ING2 requires the presence of functional p53. Furthermore, we found that overexpression of p33ING2 significantly downregulated the expression of Bcl-2 after UVB irradiation, resulting in an increased Bax/Bcl-2 ratio. Moreover, we found that p33ING2 promoted Bax translocation to mitochondria, altered the mitochondrial membrane potential, and induced cytochrome c release and thus the activation of caspases 9 and 3. In addition, we showed that under non-stress conditions p33ING2 upregulates Fas expression and activates caspase 8. Taken together, we demonstrate that p33ING2 cooperates with p53 to regulate apoptosis via activation of both the mitochondrial/intrinsic and death-receptor/extrinsic apoptotic pathways.
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PMID:The novel tumor suppressor p33ING2 enhances UVB-induced apoptosis in human melanoma cells. 1574 97

The lack of suitable criteria to predict the response to chemo- and or radiotherapy for individual patients with squamous cell carcinoma of the head and neck (HNSCC) remains still a major problem. This study was conducted to analyze prognostic significance of mitotic and apoptotic index and the DNA flow cytometric analysis of HNSCC to the recurrence-free survival time and to the overall survival. The analysis was carried out in a set of 56 patients suffering from carcinoma of the pharynx and supraglottis. Most patients (96.7%) underwent neoadjuvant chemotherapy, followed by surgery and postoperative irradiation. Besides routine examinations, flow cytometric analysis was performed, as well as p53 and Ki-67 markers and mitotic and apoptotic index were established by means of immunohistochemistry. Event-free survival (EFS) and overall survival (OS) were accepted as primary endpoints for the prognostic analyses. All the examined potential markers entered standard Kaplan-Meier survival analysis and Cox regression modeling. Statistical significance of prognostic factors was first examined in univariate models and all the parameters subsequently entered multivariate models. The analyses revealed significant prognostic position of advanced clinical stage (III+IV) and increased proliferative activity as primary risk factors (p<0.01) that typically positively correlate with increased mitotic activity and G2/M cell fraction. Better survival results obtained for grade 3-4 as compared to grade 1-2 were caused by molecular parameters that make these samples similar to less risk cases. Cytokinetic parameters and proliferation activity were found as important predictors of the second level (after recognizing stage, grade and DNA status of the tumor). Multivariate combination of these markers contributed namely to the prognosis of early risk event: a ratio S phase cell fraction/G2M cell fraction was found to be the key prognostic factor (p<0.01). Early risk events are associated with increased mitotic activity, decreased apoptic rate, decreased S phase cell fraction and significantly increased G2/M fraction.
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PMID:Prognostic significance of mitotic and apoptotic index and the DNA cytometry in head and neck cancer. 1587 80

The aetiology of squamous cell carcinomas of the head and neck (HNSCC) is multifactorial. Oncogenic human papillomaviruses (HPVs), a causative agent in uterine cervical cancer, have also been repeatedly detected in HNSCC, especially in squamous cell carcinomas of tonsils. Approximately half the HPV DNA-positive HNSCC contain detectable E6/E7 transcripts with wild-type p53, reduced pRb and overexpressed p16 in the tumours. HPV-16 is the predominant type and exists in episomal, integrated, or mixed forms. Tonsillar carcinomas have a remarkably higher viral load than carcinomas at other sites of the head and neck region. HPV-16 DNA has also been detected in tumour-free tonsils. Infection by oncogenic HPVs is a necessary but not a sufficient cause of cancers. Studies on the molecular mechanisms underlying HPV-associated carcinogenesis are difficult, because HPV is not easy to propagate in vitro. HPV-immortalised human tonsillar epithelial cell lines may provide an in vitro model to study co-factors for the HPV-associated tonsillar cancers and to test the effects of anti-viral and anti-tumour agents.
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PMID:Human papillomavirus type 16 in head and neck carcinogenesis. 1594 78

p33ING1b induces cell cycle arrest and stimulates DNA repair, apoptosis and chemosensitivity. The magnitude of some p33ING1b effects may be due to activation of the tumor suppressor p53. To investigate if the p33ING1b protein affected chemosensitivity of osteosarcoma cells, we overexpressed p33ING1b in p53+/+ U2OS cells or in p53-mutant MG63 cells, and then assessed for growth arrest and apoptosis after treatment with etoposide. p33ING1b increased etoposide-induced growth inhibition and apoptosis to a much greater degree in p53+/+ U2OS cells than in p53-mutant MG63 cells. Moreover, ectopic expression of p33ING1b markedly upregulated p53, p21WAF1 and bax protein levels and activated caspase-3 protein kinase in etoposide-treated U2OS cells. Together, our data indicate that p33ING1b prominently enhances etoposide-induced apoptosis through p53-dependent pathways in human osteosarcoma cells. p33ING1b may be an important marker and/or therapeutic target in the prevention and treatment of metastatic osteosarcoma.
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PMID:The p33ING1b tumor suppressor cooperates with p53 to induce apoptosis in response to etoposide in human osteosarcoma cells. 1632 12

p33ING2 is a novel candidate tumor suppressor, which has been shown to be involved in the regulation of gene transcription, cell cycle arrest, and apoptosis in a p53-dependent manner for maintaining the genomic stability. Previously, we showed that p33ING2 promoted UV-induced apoptosis in human melanoma cells. To further reveal the role of p33ING2 in cellular stress response to UV irradiation, we hypothesized that p33ING2 may enhance the repair of UV-damaged DNA, similarly to its homologue p33(ING1b). Using the host-cell reactivation assay, we show that overexpression of p33ING2 significantly enhances nucleotide excision repair of UV-induced DNA damage in melanoma cells in a p53-dependent manner. Furthermore, DNA repair is completely abolished in cells treated with p33ING2 small interfering RNA, suggesting that a physiologic level of p33ING2 is required for nucleotide excision repair. In addition, we found that p33ING2 is an essential factor for UV-induced rapid histone H4 acetylation, chromatin relaxation, and the recruitment of damage recognition protein, xeroderma pigmentosum group A protein, to the photolesions. These observations suggest that p33ING2 is required for the initial DNA damage sensing and chromatin remodeling in the nucleotide excision repair process.
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PMID:The novel tumor suppressor p33ING2 enhances nucleotide excision repair via inducement of histone H4 acetylation and chromatin relaxation. 1648 87

The novel ING tumor-suppressor family proteins (ING1-5) have been discovered during the past decade and are recognized as the regulators of transcription, cell cycle checkpoints, DNA repair, apoptosis, cellular senescence, angiogenesis, and nuclear phosphoinositide signaling. ING proteins contain a few conserved domains, including plant homeodomain motif, nuclear localization signal, and potential chromatin regulatory domain, suggesting that the ING family proteins may share common biological functions. ING3 has been shown to modulate p53-mediated transcription, cell cycle control, and apoptosis, possibly by modulating the NuA4 complex histone acetyltransferase activity. Because ING1b and ING2 have been shown to be involved in cellular stress responses such as nucleotide excision repair and apoptosis after UV irradiation, we investigated whether ING3 also mediated UV-induced apoptosis. We found that ING3 expression was rapidly induced by UV irradiation at both mRNA and protein levels. Using the stable clones of melanoma cells overexpressing ING3, we showed that overexpression of ING3 significantly promoted UV-induced apoptosis. Unlike its homologues ING1b and ING2, ING3-increased apoptosis was independent of functional p53. Furthermore, ING3 did not affect the expression of mitochondrial proteins but increased the cleavage of Bid and caspases-8, -9, and -3. Moreover, ING3-mediated apoptosis was blocked by inhibition of caspase-8 or Fas activation. In addition, ING3 up-regulated Fas expression at both mRNA and protein levels. Knock down of ING3 decreased UV-induced apoptosis remarkably. These data indicate that ING3 plays an important role in cellular response to UV irradiation by enhancing UV-induced apoptosis through the activation of Fas/caspase-8 pathway.
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PMID:ING3 promotes UV-induced apoptosis via Fas/caspase-8 pathway in melanoma cells. 1652 Mar 80

Squamous cell carcinoma of the head and neck (HNSCC) is a heterogeneous but largely preventable disease with complex molecular abnormalities. It arises from a premalignant progenitor followed by outgrowth of clonal populations associated with cumulative genetic alterations and phenotypic progression to invasive malignancy. These genetic alterations result in inactivation of multiple tumour suppressor genes and activation of proto-oncogenes, including p16(ink4A), p53, cyclin D1, p14(ARF), FHIT, RASSF1A, epidermal growth factor receptor (EGFR), and Rb. Intramucosal migration and clonal expansion of transformed cells with formation of abnormal genetic fields appear to be responsible for local recurrences and development of second primary tumours.
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PMID:Molecular biology of squamous cell carcinoma of the head and neck. 1664 82

ING proteins affect apoptosis, growth, and DNA repair by transducing stress signals such as DNA damage, binding histones, and subsequently regulating chromatin structure and p53 activity. p53 target genes, including the p21 cyclin-dependent kinase inhibitor and Bax, an inducer of apoptosis, are regulated by ING proteins. To identify additional targets downstream of p33ING1 and p32ING2, cDNA microarrays were performed on phenotypically normal human primary fibroblasts. The 0.36% of genes affected by ING proteins in primary fibroblasts were distinct from targets seen in established cells and included the HSP70 heat shock gene, whose promoter was specifically induced >10-fold. ING1-induced expression of HSP70 shifted cells from survival to a death pathway in response to tumor necrosis factor alpha (TNF-alpha), and p33ING1b protein showed synergy with TNF-alpha in inducing apoptosis, which correlated with reduced NF-kappaB-dependent transcription. These findings are consistent with previous reports that HSP70 promotes TNF-alpha-mediated apoptosis by binding I-kappaBeta kinase gamma and impairing NF-kappaB survival signaling. Induction of HSP70 required the amino terminus of ING1b but not the plant homeodomain region that was recently identified as a histone binding domain. Regulation of HSP70 gene expression by the ING tumor suppressors provides a novel link between the INGs and the stress-regulated NF-kappaB survival pathway important in hypoxia and angiogenesis.
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PMID:HSP70 induction by ING proteins sensitizes cells to tumor necrosis factor alpha receptor-mediated apoptosis. 1703 Jun 16


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