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)

Tumor hypoxia has been reported to be a negative prognostic factor in a number of tumor sites. Both clinical and experimental studies have suggested a positive correlation between tumor hypoxia and increased metastatic efficiency; however, the mechanisms are not understood. In this study, the mechanisms of hypoxia-enhanced metastasis have been investigated in murine KHT fibrosarcoma and SCC VII cells. We have observed that hypoxia-pretreated KHT-C cells have a higher survival rate than control KHT-C cells after being arrested in mouse lungs. cDNA microarray analysis revealed many hypoxia-regulated genes, most of which have been reported to be involved in cell survival and growth. Among these genes, we have confirmed the up-regulation of Mdm2 by hypoxia and have demonstrated that this up-regulation is p53 independent. The up-regulation of Mdm2 by hypoxia is associated with decreased p53 protein and inhibition of the transactivation of p53 downstream proapoptotic genes. Overexpression of Mdm2 or suppression of p53 by transient transfection increased metastatic efficiency in KHT-C cells. These data suggest that hypoxia can increase tumor cell metastatic efficiency by rendering the tumor cells less sensitive to stress-induced cell death, e.g., through modifying the levels of Mdm2 and p53.
 ...
PMID:Hypoxia enhances metastatic efficiency by up-regulating Mdm2 in KHT cells and increasing resistance to apoptosis. 1520 29

Overexpression of hypoxia inducible factor-1alpha (HIF-1alpha) in cancers has been correlated to a more aggressive tumor phenotype. We investigated the effect of HIF-1alpha knockout on the in vitro survival and death of human tongue squamous cell carcinomas (SCC-4 and SCC-9). Under normoxic condition, a basal level of HIF-1alpha protein was constitutively expressed in SCC-9 cells, albeit an undetectable level of HIF-1alpha messages. Exposure to hypoxia induced only a transient increase in mRNA transcript but a prolonged elevation of HIF-1alpha protein and its immediate downstream target gene product, VEGF. Under normoxic or hypoxic conditions, treatment of SCC-9 cells with AS-HIF-1alpha ODN suppressed both constitutive and hypoxia-induced HIF-1alpha expression at both mRNA and protein levels. Knockout of HIF-1alpha gene expression via either AS-HIF-1alpha ODN or siRNA (siRNAHIF-1alpha) treatment resulted in inhibition of cell proliferation and induced apoptosis in SCC-4 and SCC-9 cells. We also demonstrated that exposure of SCC-9 cells to hypoxia led to a time-dependent increase in the expression of bcl-2 and IAP-2, but not p53. The attenuated levels of bcl-2 and IAP-2, and the enhanced activity of caspase-3 after treatment with AS-HIF-1alpha ODN may contribute partly to the effects of HIF-1alpha blockade on SCC-9 cell death. Collectively, our data suggest that a constitutive or hypoxia-induced expression of HIF-1alpha in SCC-9 and SCC-4 cells is sufficient to confer target genes expression essential for tumor proliferation and survival. As a result, interfering with HIF-1alpha pathways by antisense or siRNA strategy may provide a therapeutic target for human tongue squamous cell carcinomas.
 ...
PMID:Treatment with siRNA and antisense oligonucleotides targeted to HIF-1alpha induced apoptosis in human tongue squamous cell carcinomas. 1530 Jul 96

A polymorphism at codon 72 of the human tumor suppressor p53 determines translation into either arginine or proline. Yet, the impact of this amino acid variability on the risk to develop malignant tumors, particularly carcinomas associated with human papilloma virus (HPV) infections, remains unresolved because of contradictory results. To address a potential correlation between the different genotypes and the manifestation of squamous cell carcinomas of the head and neck (SCCHN), we determined the p53 codon 72 in 193 healthy subjects and 122 unselected SCCHN with known HPV status. Furthermore, loss of allele-specific transcription was analyzed in p53 codon 72 heterozygous (Arg/Pro) SCCHN and correlated with HPV 16 and/or 18 E6 transcript expression. We found a moderately increased risk (odds ratio, 1.86; 95% confidence interval, 1.0-3.3) for individuals with germ line heterozygosity to develop SCC of the pharynx. On the other hand, p53 codon 72 polymorphic variants, most notably the Arg/Arg genotype, showed no association with the presence of HPV 16 and/or 18 E6 transcript. Moreover, there was no evidence for HPV-driven selection in SCCHN with allele-specific loss of transcription. Our data suggest that the p53 codon 72 polymorphism has a minor impact on the development of SCCHN.
 ...
PMID:p53 codon 72 polymorphic variants, loss of allele-specific transcription, and human papilloma virus 16 and/or 18 E6 messenger RNA expression in squamous cell carcinomas of the head and neck. 1553 11

The aim of this study was to determine the effect of ZD1839 on growth and apoptosis in SCC-15 (a human head and neck cancer cell line) lone, or in combination with cisplatin. High expression of the epidermal growth factor receptor has been implicated in the development of squamous cell carcinomas of head and neck. ZD1839 ('Iressa') is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor that blocks signal transduction pathways implicated in proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. Here, growth arrest was observed with 3.64 microm ZD1839. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (sMTT) viability assay revealed a significant decrease (P < 0.001) in the percentage of surviving cells upon treatment with ZD1839 and cisplatin compared with cisplatin or ZD1839 on their own. Combined therapy of 3.64 microm ZD1839 for 24 h, prior to administration of 100 microm cisplatin, significantly (P < 0.001) and additively increased the cytotoxicity effect of cisplatin. p53-independent apoptosis was seen with cisplatin treatment, a novel finding. These data support the use of ZD1839 in anti-cancer therapy, and particularly in combination therapy. Cisplatin may induce p53-independent apoptosis. Over-expression of Bcl-2 in head and neck squamous cell carcinoma tumour cell lines is unlikely to be a general mechanism to protect these cells from apoptosis.
 ...
PMID:The effect of ZD1839 (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor, in combination with cisplatin, on apoptosis in SCC-15 cells. 1584 52

We analyzed survivin as a marker of cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus (HR-HPV) and a predictor of HPV clearance and disease outcome in cervical cancer in 302 samples (squamous cell carcinomas [SCCs], 150; CIN lesions, 152) by immunohistochemical staining with survivin antibody and HPV testing using polymerase chain reaction. HR-HPV types were associated closely with CIN and SCC. There was a significant linear relationship between grade and intensity of survivin expression (P = .0001). Survivin overexpression also was associated strongly with HR-HPV type (P = .0001). Multivariate regression analysis revealed survivin and p16(INK4a) as equally strong independent predictors of HR-HPV. Deregulated survivin expression did not predict clearance or persistence of HR-HPV after treatment of CIN or survival in cervical cancer in univariate (P = .417) or multivariate analysis. After adjustment for HR-HPV, stage, age, and tumor grade in the Cox regression model, only stage (P = .0001) and age (P = .0001) remained independent prognostic predictors. Survivin seems to be an early marker of cervical carcinogenesis. Up-regulated survivin expression was an independent predictor of HR-HPV in cervical lesions, most plausibly explained by its normal transcriptional repression by wild-type p53 being eliminated by HR-HPV E6 oncoprotein.
 ...
PMID:Survivin as a marker of cervical intraepithelial neoplasia and high-risk human papillomavirus and a predictor of virus clearance and prognosis in cervical cancer. 1592 64

Head and neck squamous cell carcinoma express high levels of the EF-hand calcium-binding protein S100A2 in contrast to other tumorigenic tissues and cell lines where the expression of this protein is reduced. Subtractive hybridization of tumorigenic versus normal tumor-derived mammary epithelial cells has previously identified the S100A2 protein as potential tumor suppressor. The biological function of S100A2 in carcinogenesis, however, has not been elucidated to date. Here, we report for the first time that during recovery from hydroxyurea treatment, the S100A2 protein translocated from the cytoplasm to the nucleus and co-localized with the tumor suppressor p53 in two different oral carcinoma cells (FADU and SCC-25). Co-immunoprecipitation experiments and electrophoretic mobility shift assay showed that the interaction between S100A2 and p53 is Ca(2+)-dependent. Preliminary characterization of this interaction indicated that the region in p53 involved with binding to S100A2 is located at the C terminus of p53. Finally, luciferase-coupled transactivation assays, where a p53-reporter construct was used, indicated that interaction with S100A2 increased p53 transcriptional activity. Our data suggest that in oral cancer cells the Ca(2+)- and cell cycle-dependent p53-S100A2 interaction might modulate proliferation.
 ...
PMID:The calcium-binding protein S100A2 interacts with p53 and modulates its transcriptional activity. 1594 20

Organ preservation protocols in head and neck squamous cell carcinoma (HNSCC) are limited by tumors that fail to respond. We observed that larynx preservation and response to chemotherapy is significantly associated with p53 overexpression, and that most HNSCC cell lines with mutant p53 are more sensitive to cisplatin than those with wild-type p53. To investigate cisplatin resistance, we studied two HNSCC cell lines, UM-SCC-5 and UM-SCC-10B, and two resistant sublines developed by cultivation in gradually increasing concentrations of cisplatin. The cisplatin-selected cell lines, UM-SCC-5PT and UM-SCC-10BPT, are 8 and 1.5 times more resistant to cisplatin than the respective parental cell lines, respectively. The parental lines overexpress p53 and contain p53 mutations but the cisplatin-resistant cell lines do not, indicating that cells containing mutant p53 were eliminated during selection. Bcl-x(L) expression increased in the cisplatin-resistant lines relative to the parental lines, whereas Bcl-2 expression was high in the parental lines and decreased in the cisplatin-resistant lines. Thus, cisplatin selected for wild-type p53 and high Bcl-x(L) expression in these cells. We tested a small-molecule BH3 mimetic, (-)-gossypol, which binds to the BH3 domain of Bcl-2 and Bcl-x(L), for activity against the parental and cisplatin-resistant cell lines. At physiologically attainable levels, (-)-gossypol induces apoptosis in 70% to 80% of the cisplatin-resistant cells but only in 25% to 40% of the parental cells. Thus, cisplatin-resistant cells seem to depend on wild-type p53 and Bcl-x(L) for survival and BH3 mimetic agents, such as (-)-gossypol, may be useful adjuncts to overcome cisplatin resistance in HNSCC.
 ...
PMID:Reversal of cisplatin resistance with a BH3 mimetic, (-)-gossypol, in head and neck cancer cells: role of wild-type p53 and Bcl-xL. 1602 Jun 67

Human papilloma virus (HPV) infection and loss of P53 function have been identified as frequent events in various human tumors. The aim of this study was to evaluate P53 protein expression and to detect HPV in the tissue samples of 45 benign (papillomas) and 38 malignant conjunctival and eyelid lesions (27 basal cell carcinomas and 11 squamous cell carcinomas). We also looked for eventual relationships between P53 expression and clinicopathological features such as age, histological type of tumor, grading and staging. HPV infection was detected using the PCR-RFLP method. Specific primers were engaged and PCR products of HPV 16, 18, and 33, underwent enzymatic digestion at 37 degrees C. We revealed P53 protein expression in 30 out of 45 (66.6%) squamous cell papillomas. In the SCC and BCC groups, P53 was present in 31 out of 38 carcinomas and there was a statistically significant correlation between histological type of tumor and P53 protein expression. Malignant type HPV 16 and 18 were detected in three squamous cell papillomas, two BCCs and one SCC. However, we observed P53 protein expression in only two HPV-positive papillomas and one infiltrative type of BCC. P53 is probably involved in the development of conjunctival and eyelid tumors due to its high rate of presence in both benign and malignant neoplasms of these organs. HPV seems to occur rarely. In some cases its role in the pathogenesis of conjunctival and eyelid tumorigenesis should be considered as auxiliary.
 ...
PMID:The expression of P53 protein and infection of human papilloma virus in conjunctival and eyelid neoplasms. 1614 87

Alterations in expression of retinoid receptors are implicated in human cancers. We hypothesized that altered expression of retinoic acid receptors (RARalpha,beta,gamma) and retinoid X receptor RXRalpha and their relationship with cell cycle regulators (p53, p16, p21) is associated with development, progression and prognosis of oral cancer. Immunohistochemical analysis of RAR alpha, beta, gamma and RXRalpha proteins was carried out on serial sections from 244 oral squamous cell carcinomas (OSCCs), 102 potentially malignant lesions (65 hyperplasias, 37 dysplasias), 83 matched histologically normal oral tissues and 29 normal mucosa from non-exposed individuals without oral lesions and correlated with expression of cell cycle regulators p53, p16 and p21 as well as with clinicopathological parameters. Expression of retinoid receptors RARbeta, RARgamma, RXRalpha and cell cycle regulators p16 and p21 was decreased in majority of oral SCCs as well as in potentially malignant lesions. Multivariate stepwise logistic regression analysis carried out for comparison of non-exposed normal oral mucosa with histologically normal oral tissues from patients with oral lesions showed significant loss of RARbeta or p53 accumulation (RARbeta(-)/p53(+) Odd's ratio, OR = 266.6, p = 0.000); non-exposed normal mucosa from individuals without oral lesions with potentially malignant lesion was RARbeta(-)/p21(-)/p53(+) (OR = 215.7, p = 0.000); matched normal to potentially malignant stage was RARalpha(+)/p21(-) (OR = 4.414, p = 0.005); hyperplasia to dysplasia was RARalpha(+)/p53(+) (OR = 4.72, p = 0.005) and potentially malignant to malignant phenotype was RARalpha(+) (OR = 2.061, p = 0.004). The prognostic relevance of these factors was assessed in 115 of these SCC patients who were followed-up for a maximum period of 94 months (median 21 months). Multivariate analysis using Cox's proportional Hazard's model showed that RARalpha(+)/p21(-) phenotype was associated with shorter disease-free survival (Hazard's ratio, HR = 1.863, p = 0.0471). To our knowledge, this is the first large study showing alterations in expression of retinoid receptors at the protein level at different stages in development and progression of oral SCC. It also underscored the prognostic significance of retinoid receptors and their interactions with cell cycle regulators in multistep oral tumorigenesis.
 ...
PMID:Clinical significance of altered expression of retinoid receptors in oral precancerous and cancerous lesions: relationship with cell cycle regulators. 1616 Oct 51

The human p63 gene encodes a series of proteins that differ in their N- and/or C-terminal sequences and have widely differing properties in promoting or repressing p53-related functions such as growth arrest and apoptosis. In addition, p63 has important roles in the maintenance and differentiation of epithelial cell populations. Squamous cell carcinomas of the head and neck (SCCHN) express high levels of DeltaNp63 and p63beta isoforms compared to normal tissue from the same patients, suggesting a role for these isoforms in the pathogenesis of this common human malignancy. Here, we explore the function of p63 in SCCHN cells by using small interfering RNA (siRNA) to silence the expression of different isoforms in two SCCHN cell lines, FaDu and SCC-25. Silencing results in statistically significant decreased survival for tumour cells when all p63 isoforms, the N-terminal truncated or the alpha isoforms are inhibited. No effect was observed on cell proliferation or on the expression of epithelial differentiation markers. We also demonstrate that inhibition of endogenous p63 expression sensitises cells to the effects of ionizing radiation and cisplatin, common treatments for SCCHN patients. The data indicate that p63 has oncogenic properties in SCCHN and is predominantly involved in maintaining cell survival, rather than acting as a directly proliferative factor or as an inhibitor of terminal differentiation. Moreover, targeted inhibition of p63 expression in SCCHN could be a useful adjunct for conventional treatments of this disease.
 ...
PMID:Endogenous p63 acts as a survival factor for tumour cells of SCCHN origin. 1627 87


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