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)

Taxol is one of the most successful drugs for the treatment of cancer because of its ability to target tubulin, block cell cycle progression at mitosis, and induce apoptosis. Despite the success of Taxol, the development of drug resistance hampers its clinical applicability. Herein we report that beta-tubulin mutant, Taxol-resistant ovarian cancer cells exhibit defective mitotic response to Taxol, even at high concentrations that are sufficient to trigger apoptosis. This mitotic response-defective phenotype is independent of p53 status. We have found that survivin, the mitosis regulator and inhibitor of apoptosis protein, is deregulated in these Taxol-resistant cancer cells; Taxol fails to induce survivin levels and survivin phosphorylation in these cells, in contrast to their parental drug-sensitive counterparts. Exogenous expression of wild-type survivin is able to restore the mitotic response of the resistant cells to Taxol treatment. On the other hand, exogenous expression of dominant-negative survivin abrogates the Taxol-induced mitotic response in drug-sensitive cancer cells. We have also found that overexpression of the mitotic kinase Cdk1, which phosphorylates survivin, is unable to restore the Taxol-induced mitotic response in the resistant cells. Our results show the importance of survivin for the mitotic response in the context of Taxol resistance and provide novel insights into the mechanisms of mitotic arrest and apoptosis induced by microtubule-targeting agents.
 ...
PMID:Survivin deregulation in beta-tubulin mutant ovarian cancer cells underlies their compromised mitotic response to taxol. 1557 81

Survivin, a member of the inhibitor-of-apoptosis family is an essential protein for regular mitosis and is involved in an anti-apoptotic pathway. In some studies, an association between survivin expression and radiosensitivity has been described for tumor cells, but the relationship between p53 and survivin regarding radioresistance remains to be clarified. In order to increase the effect of irradiation on two sarcoma cell lines, A-204 with wt-p53 and US 8-93 with mt-p53, siRNA was applied to knock down survivin expression. The effects of combined treatment of siRNA treatment and irradiation were investigated by clonogenic survival assay, measurement of activity of caspases 3 and 7, Western blot hybridization for survivin and p53, and morphological analysis of apoptosis. Survivin knock down caused radiosensitization in the cell line A-204 (wt-p53) with an enhancement factor of 1.8 at 2 Gy (p=0.05) and 2.5 at 4 Gy (p=0.02), respectively. No radiosensitization was found in the cell line US 8-93 (mt-p53), when clonogenic survival was analyzed. These findings were supported by an increase in activity (up to 5.2-fold) of caspases 3 and 7 in cell line A-204 (wt-p53), but not in cell line US 8-93 (mt-p53) after a combined treatment of siRNA and irradiation. Our findings suggest that the wt-p53-caspase pathway is of importance for the radiosensitization induced by targeting survivin, which may have an impact on future gene therapeutical treatments.
 ...
PMID:Radiosensitization, after a combined treatment of survivin siRNA and irradiation, is correlated with the activation of caspases 3 and 7 in a wt-p53 sarcoma cell line, but not in a mt-p53 sarcoma cell line. 1558 20

We investigated the association of survivin expression with prognosis and other apoptosis-related biological factors in 110 primary ovarian cancer patients admitted to the Division of Gynecologic Oncology, Catholic University of Rome. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections by using polyclonal antibody ab469 for survivin, and mouse monoclonal antibodies (clone 124 and DO-7), for bcl-2 and p53, respectively. Cytoplasmic survivin immunoreaction was observed in 84.5% cases, while nuclear survivin immunostaining was observed in 29.1% cases. We failed to find any relationship between cytoplasmic survivin positivity rate and any of the parameters examined. Serous tumours showed a lower percentage of nuclear survivin positivity with respect to other histotypes (20.5 vs 48.6%, respectively; P-value=0.004). The percentage of nuclear survivin positivity was higher in cases subjected to primary tumour cytoreduction (43.5%), with respect to patients subjected to exploratory laparotomy (20%) (P=0.024). Bcl-2 and p53 were, respectively, expressed in 27.3 and 60.0% of the cases and their expression was not correlated with survivin status. During the follow-up period, progression and death of disease were observed in 68 (61.8%) and 53 (48.2%) cases, respectively. There was no difference in time to progression and overall survival according to survivin status in ovarian cancer patients. In conclusion, in our experience, the immunohistochemical assessment of survivin status does not seem to be helpful in the prognostic characterisation of ovarian cancer. A more in depth investigation of the complex physiology of divergent survivin variants is needed in order to clarify the biological and the clinical role of differentially located survivin isoforms.
 ...
PMID:Survivin expression in ovarian cancer and its correlation with clinico-pathological, surgical and apoptosis-related parameters. 1565 41

DNA (cytosine-5)-methyltransferase (DNMT) 1 participates in transcriptional repression of genes by methylation-dependent and -independent mechanisms. Here, DNMT1 is shown to bind p53 and colocalize in the nucleus. DNMT1-mediated methylation is stimulated by p53 in vitro. Upon p53 induction, a reporter construct containing the antiapoptotic gene survivin promoter, which contains a natural p53 binding site, was methylated in WT HCT116 cells but not in DNMT1 null or p53 null cells. Endogenous survivin gene repression involves cooperation between DNMT1 and p53 and is relieved by introduction of DNMT1- or p53-specific small inhibitory RNA. DNMT1 null cells did not exhibit a significant repressive effect for p53 responsive survivin and cdc25C gene expression compared with the parental cells. Normal human fibroblasts also exhibited similar DNMT1- and p53-mediated methylation of the survivin promoter, suggesting cooperation between p53 and DNMT1 in gene silencing.
 ...
PMID:Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters. 1565 47

As more and more effective targeted therapeutics have been developed to treat adults with cancer, it is of critical importance to devise appropriate in vitro experimental models to study their use in pediatric patients. Acute lymphoblastic leukemia (ALL) with Bcr-Abl translocation is one of the most difficult to treat and deadly diseases in children. The targeted kinase inhibitor imatinib mesylate has been shown to induce an initial response but resistance often develops. Recently, the geldanamycin family of antibiotics has been found to induce apoptosis in many malignant cells, including adult CML and AML. We describe experiments in which 17-allylamino-17-demethoxygeldanamycin (17-AAG) was evaluated in the context of Bcr-Abl and resistance to imatinib mesylate. Pediatric ALL cell lines with varying Bcr-Abl status and imatinib mesylate sensitivity were generated and their growth inhibition by 17-AAG was studied in vitro. Western blots were used to follow the changes in proteins that correlate with cell survival. Results show that apoptosis was induced in all lines with an increased 50% inhibitory concentration (IC50) for Bcr-Abl positive but imatinib mesylate-resistant cells. Addition of 17-AAG greatly increased imatinib sensitivity in vitro. A decrease in p53, survivin, Her2/neu, and WT1 was seen in cells that expressed these proteins. With some notable exceptions, when combined with 17-AAG, the IC50 of most of the common chemotherapeutic agents decreased. We describe an experimental approach to investigate the complex interaction between Bcr-Abl status, imatinib mesylate sensitivity, and 17-AAG in pediatric ALL. Information from such an approach will provide means to devise combined treatment approaches and to follow their effectiveness in vitro.
 ...
PMID:Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) on pediatric acute lymphoblastic leukemia (ALL) with respect to Bcr-Abl status and imatinib mesylate sensitivity. 1565 98

Development of novel approaches for quantitative analysis of gene expression in intact tumor cells should provide new means for cancer detection and for studying the response of cancer cells to biological and therapeutic reagents. We developed procedures for detecting the levels of expression of multiple genes in fixed as well as viable cells using molecular beacon imaging technology. We found that simultaneous delivery of molecular beacons targeting survivin and cyclin D1 mRNAs produced strong fluorescence in breast cancer but not in normal breast cells. Importantly, fluorescence intensity correlated well with the level of gene expression in the cells detected by real-time reverse transcription-PCR or Western blot analysis. We further show that molecular beacons can detect changes of survivin gene expression in viable cancer cells following epidermal growth factor stimulation, docetaxel treatment, and overexpression of p53 gene. Thus, molecular beacon imaging is a simple and specific method for detecting gene expression in cancer cells. It has great potential for cancer detection and drug development.
 ...
PMID:Real-time detection of gene expression in cancer cells using molecular beacon imaging: new strategies for cancer research. 1575 90

The World Health Organization Classification of Lymphoid Neoplasms identifies Burkitt's lymphoma/leukaemia (BL) as a single entity, characterized by unique clinical and genetic features that require specific high intensity chemotherapy regimens. Although remarkable successes in the treatment of the disease have been observed, when compared with paediatric patients, adults are less likely to reach stable complete remission. We investigated 32 BL cases, composed in equal part by adults and children that were treated with the French LMB regimen, for factors that may be implicated in chemoresistance. Immunohistochemical detection of procaspase-8, caspase-3a, survivin, p53, CD95, c-Flip and Phospho-RelA (Ser536) was investigated on paraffin-embedded tissues. The expression of c-Flip was found highly related to a poor prognosis, mostly characterized by adults with a chemoresistant disease, resulting in a high death rate within the first year of diagnosis. The 2-year overall survival with c-Flip expression was 24% compared with 93% in the absence of this marker (P = 0.04). All c-Flip-positive BL cases presented a nuclear Phospho-RelA (Ser536) localization, suggesting the presence of an active nuclear factor (NF)-kappa B transcription pathway. These findings show that c-Flip could be a reliable prognostic factor in BL, suggesting new therapeutic approaches that target the NF-kappa B pathway.
 ...
PMID:c-Flip protein expression in Burkitt's lymphomas is associated with a poor clinical outcome. 1575 79

Classical Hodgkin lymphomas (cHL) have now been recognized as B-cell lymphomas with some exceptional cases of T-cell origin. In recent years, there has been accumulating evidence that Hodgkin and Reed-Sternberg (H/RS) cells, the presumed neoplastic-cell population in cHL, are characterized by a profound disturbance of the cell cycle and apoptosis regulation. The constitutive activation of the nuclear factor (NF)-kappaB pathway, which is considered to be involved in the proliferation and survival of H/RS cells. Moreover, substantial evidence that H/RS cells have defective cell cycle and apoptosis regulation has been provided by studies showing that these cells are characterized, in a large proportion of cases, by alterations of the p53, Rb and p27 tumor suppressor pathways, overexpression of cyclins involved in the G1/S and G2/M transition such as cyclins E, D2, D3, A and B1, overexpression of cyclin-dependent kinases such as CDK1, 2 and 6 and overexpression of anti-apoptotic proteins such as c-FLIP, bcl-xl, c-IAP2, X-linked I4P and survivin. Recent studies suggest that interleukin 13 (IL-13) is an important growth and survival factor in H/RS cells. Furthermore, the Epstein-Barr Virus (EBV), which is present in H/RS cells in about 30-50% of cHL, has been shown to affect the cell cycle and apoptosis regulation in cHL. The present review summarizes data with respect to the cell cycle and apoptosis deregulation in cHL.
 ...
PMID:Cell cycle and apoptosis deregulation in classical Hodgkin lymphomas. 1579 9

To test the hypothesis that AURKA amplification contributes to pancreatic tumorigenesis by increasing centrosome abnormality and chromosome instability, the current study explored the associations between AURKA amplification, chromosome instability, centrosome abnormality, and the expression of several important proteins that are involved in cell proliferation (Ki-67), cell cycle regulation (p53, p16), and apoptosis (survivin) in 12 human pancreatic carcinoma cell lines. Using fluorescence in situ hybridization (FISH), we observed that 5 of the 12 cell lines had an AURKA amplification index (AI) (percentage of cells with more than three signals) >60%. Both the AURKA AI and the average number of signals per cell (ANSPC) were significantly associated with the copy number of chromosome 9 but not chromosome 17. The AURKA ANSPC was positively associated with the percentage of cells with the centrosome abnormality. Furthermore, centrosome abnormality was significantly associated with the frequency of cells with abnormal nuclei and abnormal mitotic figures, but no direct association was detected between the frequency of centrosome abnormalities and chromosome instabilities. The AURKA AI was also associated with a lower expression of Ki-67, a higher expression of survivin, and the lack of expression of p16. These associations support our hypothesis that AURKA amplification contributes to pancreatic carcinogenesis by increasing chromosome instability and centrosome abnormality.
 ...
PMID:AURKA amplification, chromosome instability, and centrosome abnormality in human pancreatic carcinoma cells. 1586 Mar 51

A model system of cultivated melanoma cells and melanomas from patients were used in this study to clarify whether survivin protein was involved in UVB induced cell damage and in melanoma progression. The melanoma cells in culture were exposed to different doses of UVB and post-cultivated for various periods of time. Cell viability, apoptotic index and expression of survivin proteins were estimated. Expression of the survivin in normal tissue, nevi, primary and metastatic melanomas from the patients were also examined by immunohistochemistry. Results showed that UVB induced cell damage and apoptosis in melanoma cells. Primary and wt p53 cells were more sensitive than metastatic and mutant p53 melanoma cells. Expression of survivin protein was markedly decreased in the primary melanoma cells after exposure to UVB compared to the metastasis. The expression was markedly decreased in wt p53 melanoma cells, but not in the mutant p53 melanoma cells. Survivin protein was expressed in nevi, primary and metastatic melanomas. However, the normal tissues were not expressed in the survivin protein. Survivin plays an important role in UVB-induced apoptosis. Overexpression of survivin might be a biomarker for early diagnosis for melanoma.
 ...
PMID:Survivin protein in UVB induced apoptosis of melanoma cells and in melanoma progression. 1587 Sep 31


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