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)

Survivin is an inhibitor of apoptosis protein, which is over-expressed in most tumors. Aberrant expression of survivin and loss of wild-type p53 in many tumors prompted us to investigate a possible link between these two events. Here we show that wild-type p53 represses survivin expression at both mRNA and protein levels. Transient transfection analyses revealed that the expression of wild-type p53, but not mutant p53, was associated with strong repression of the survivin promoter in various cell types. The over-expression of exogenous survivin protein rescues cells from p53-induced apoptosis in a dose-dependent manner, suggesting that loss of survivin mediates, at least, in part the p53-dependent apoptotic pathway. In spite of the presence of two putative p53-binding sites in the survivin promoter, deletion and mutation analyses suggested that neither site is required for transcriptional repression of survivin expression. This was confirmed by chromatin immunoprecipitation assays. Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53.
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PMID:Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. 1196 34

A checkpoint surveying the entry into mitosis responds to defects in spindle microtubule assembly/stability. This has been used to trigger apoptosis in cancer cells, but how the spindle checkpoint couples to the cell survival machinery has remained elusive. Here, we report that microtubule stabilization engenders a survival pathway that depends on elevated activity of p34(cdc2) kinase and increased expression of the apoptosis inhibitor and mitotic regulator, survivin. Pharmacologic, genetic, or molecular ablation of p34(cdc2) kinase after microtubule stabilization resulted in massive apoptosis independent of p53, suppression of tumor growth, and indefinite survival without toxicity in mice. By ablating this survival checkpoint, inhibitors of p34(cdc2) kinase could safely improve the efficacy of microtubule-stabilizing agents used to treat common cancers.
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PMID:A p34(cdc2) survival checkpoint in cancer. 1215 Aug 24

Survivin is a novel member of the inhibitor of apoptosis protein (IAP) family. Here we report that the chemotherapeutic drug doxorubicin, a DNA-damaging agent, activates a p53-survivin signaling pathway inducing cell cycle arrest and apoptosis in childhood acute lymphoblastic leukemia (ALL). Treatment of wild-type (wt) p53 ALL cells (EU-3 cell line) with doxorubicin caused accumulation of p53, resulting in dramatic down-regulation of survivin, depletion of cells in G(2)/M, and apoptosis (increased sub-G(1) compartment). In contrast, doxorubicin treatment of mutant (mut) p53 cells (EU-6/ALL line) up-regulated survivin and induced G(2)/M arrest without inducing apoptosis. However, treating EU-6 with anti-survivin antisense resensitized these cells to doxorubicin, resulting in apoptosis. With a p53-null cell line (EU-4), although doxorubicin treatment arrested cells in G(2)/M, survivin expression was unchanged, and cells underwent only limited apoptosis. However, re-expression of wt-p53 in EU-4 cells could restore the doxorubicin-p53-survivin pathway, resulting in significantly decreased survivin expression and increased apoptosis in these cells after doxorubicin treatment. Following cotransfection of p53-null EU-4 cells with survivin promoter-luciferase constructs and either wt-p53 or different mut-p53 expression vectors, wt-p53 inhibited survivin promoter activity; p53-mediated inhibition could be abrogated by overexpression of murine double minute2 (MDM2) protein. Together, these studies define a novel p53-survivin signaling pathway activated by DNA damage that results in down-regulation of survivin, cell cycle arrest, and apoptosis. Furthermore, our data indicate that loss of wt-p53 function in tumor cells may contribute to up-regulation of survivin and resistance to DNA-damaging agents.
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PMID:DNA damage induces a novel p53-survivin signaling pathway regulating cell cycle and apoptosis in acute lymphoblastic leukemia cells. 1223 42

Stable transfection of human ovarian carcinoma cells with survivin cDNA caused a four- to sixfold increase in cell resistance to taxotere and taxol (two-sided Student's t test, p < 0.05), with a concomitant reduction in the apoptotic response to taxol, but did not affect cell sensitivity to cisplatin or oxaliplatin. Such findings were indirectly supported by similar observations obtained with clinical tumours. In fact, high levels of survivin protein expression (>30% positive cells), detected by immunohistochemistry in 90/124 (73%) advanced ovarian carcinomas, were significantly associated with clinical resistance to a taxol/platinum-based regimen but unrelated to tumour shrinkage following cisplatin-including combinations (non-taxol based). In the 95 patients receiving a taxol/platinum-based regimen, survivin overexpression correlated with a lower clinical or pathologic complete remission rate than absent/low protein expression (43 vs 75%, p = 0.0058 by logistic regression adjusted for tumour stage, histological grade and p53 expression). Conversely, in the 29 cases treated with cisplatin-containing regimens (not taxol based), survivin expression was unrelated to tumour response. Cellular studies and clinical data suggest a direct link between survivin expression and tumour cell susceptibility to taxol.
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PMID:Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer. 1236 43

Tumoral cells in Hodgkin lymphoma (HL) display an increased growth fraction and diminished apoptosis, implying a profound disturbance of the cell cycle and apoptosis regulation. However, limitations of molecular techniques have prevented the analysis of the tumor suppressor pathways and cell-cycle checkpoints. Tissue microarray (TMA) is a powerful tool for analyzing a large number of molecular variables in a large series of tumors, although the feasibility of this technique has not yet been demonstrated in heterogeneous tumors. The expression of 29 genes regulating the cell cycle and apoptosis were analyzed by immunohistochemistry and in situ hybridization in 288 HL biopsies using TMA. The sensitivity of the technique was validated by comparing the results with those obtained in standard tissue sections. The results revealed multiple alterations in different pathways and checkpoints, including G1/S and G2/M transition and apoptosis. Striking findings were the overexpression of cyclin E, CDK2, CDK6, STAT3, Hdm2, Bcl2, Bcl-X(L), survivin, and NF-kappaB proteins. A multiparametric analysis identified proteins associated with increased growth fraction (Hdm2, p53, p21, Rb, cyclins A, B1, D3, and E, CDK2, CDK6, SKP2, Bcl-X(L), survivin, STAT1, and STAT3), and proteins associated with apoptosis (NF-kappaB, STAT1, and RB). The analysis also demonstrated that Epstein-Barr virus (EBV)-positive cases displayed a characteristic profile, confirming the pathogenic role of EBV in HL. Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index. In conclusion, Hodgkin and Reed-Sternberg cells harbor concurrent and overlapping alterations in the major tumor suppressor pathways and cell-cycle checkpoints. This appears to determine the viability of the tumoral cells and the clinical outcome.
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PMID:Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays. 1239 83

Recurrent respiratory papillomatosis (RRP), caused by the human papillomavirus, is characterized by unregulated growth of wartlike neoplasms on laryngeal mucosa. Apoptosis is important in normal cellular homeostasis, and dysregulation of this process is thought to govern the behavior of certain neoplasms. This study evaluates the expression of several pro-apoptotic and anti-apoptotic factors in papillomas of patients with RRP, with a specific interest in survivin, a cell cycle-regulated anti-apoptotic factor. Three anti-apoptotic and 6 pro-apoptotic messenger RNA (mRNA) species were quantified by ribonuclease protection assay in 11 RRP papilloma specimens and 5 normal laryngeal specimens. Anti-apoptotic and pro-apoptotic mRNA ratios were quantified by normalizing to the ribosomal protein L32 and compared between specimens. Protein expression of survivin in tissue samples was also evaluated. The mean (+/- SD) expression of survivin was almost fivefold greater in the RRP papillomas than in normal tissue (14.2% +/- 2.5% versus 3.0% +/- 0.8% of L32, p = .003). The RRP specimens also had greater expression of XIAP, Fas, and p53 than did the normal tissue. Survivin protein was differentially expressed in the papilloma specimens, and was greatest in a papilloma that underwent malignant transformation. Survivin was absent in all normal laryngeal tissue tested. Apoptotic factors in general appear to be upregulated in papillomatous tissue as compared to normal laryngeal tissue and may suggest a higher proliferation rate and cell turnover. Survivin is abundant in papillomas and absent in normal laryngeal tissue. Dysregulation of apoptosis as determined by abnormal expression of anti-apoptotic factors like survivin and XIAP probably favors papilloma growth and survival. Such factors may represent potential targets in the treatment of this disease.
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PMID:Survivin expression in juvenile-onset recurrent respiratory papillomatosis. 1245 Jan 66

The members of the IAP (inhibitors of apoptosis) family, which includes survivin, have recently emerged as modulators of an evolutionarily conserved step in apoptosis. Survivin is present during embryonic and fetal development, but it is downregulated in normal adult tissues. However, it becomes re-expressed in a variety of cancers. We investigated the prognostic importance of the expression of survivin in transitional cell carcinoma of the upper urinary tract (TCC-UUT). In 126 cases of TCC-UUT, we examined its expression (using immunohistochemistry), and also its relationship with the expressions of bcl-2 oncoprotein, p53 oncoprotein, and proliferating cell nuclear antigen (PCNA) immunoreactivity, clinicopathologic parameters, and clinical outcome. A positive expression of survivin was recognized in 12.7% of samples, a granular pattern being apparent within the cytoplasm of tumor cells. Survivin expression did not correlate with clinicopathologic findings, bcl-2 oncoprotein expression, p53 oncoprotein expression, PCNA index, or prognosis. In the normal urothelium, its expression was not detected. In conclusion, the expression of survivin does not predict prognosis in TCC-UUT.
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PMID:Expression of survivin does not predict survival in patients with transitional cell carcinoma of the upper urinary tract. 1246 12

The classification of thymic epithelial tumors is controversial because prediction of the biological behavior of these tumors from their morphologic appearance is difficult. The aim of this study was to evaluate the proliferative activity and rate of apoptosis of thymic epithelial tumors classified according to World Health Organization histological classification. We also attempted to determine the importance of a number of proapoptotic factors in these processes. We investigated 46 surgically resected thymic epithelial tumors (8 Type A, 8 Type AB, 7 Type B1, 7 Type B2, 6 Type B3, and 10 Type C). Immunohistochemical staining was performed to determine the tumor expression of p53 protein, Bax, Bcl-2, and survivin. In addition, the Ki-67 labeling index (LI) and apoptotic index (AI) of these tumors were evaluated. Type C thymoma had a higher LI (16.55 +/- 12.12%) than did the other histological subtypes. Stage IV thymoma (12.36 +/- 9.99%) had a higher LI than did Stage I tumor. The AI was significantly elevated in Type B1 thymoma (1.47 +/- 0.55%). Overexpression of p53 protein was observed in Type B3 and C thymomas. p53 protein-positive tumors had a higher LI than did p53 protein-negative tumors (P <.0001). Bcl-2 expression was observed in Type A, AB, and C thymomas. Bcl-2-positive thymoma had a lower AI than did Bcl-2-negative thymoma (P =.0157). These results suggest that overexpression of p53 protein is associated with a higher tumor proliferative activity and that Bcl-2 acts as an inhibitor of apoptosis in thymoma. Bcl-2 and p53 protein expression may be useful markers in differentiating thymoma subtypes.
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PMID:Proliferative activity and apoptosis in thymic epithelial neoplasms. 1248 Oct 14

Survivin is a member of the inhibitor of apoptosis gene family that is expressed in most human cancers and may facilitate evasion from apoptosis and aberrant mitotic progression. Here, exposure of breast carcinoma MCF-7 or cervical carcinoma HeLa cells to anticancer agents, including Adriamycin, Taxol, or UVB resulted in a 4-5-fold increased survivin expression. Changes in survivin levels after anticancer treatment did not involve modulation of survivin mRNA expression and were independent of de novo gene transcription. Conversely, inhibition of survivin phosphorylation on Thr(34) by the cyclin-dependent kinase inhibitor flavopiridol resulted in loss of survivin expression, and nonphosphorylatable survivin Thr(34)-->Ala exhibited accelerated clearance as compared with wild-type survivin. Sequential ablation of survivin phosphorylation on Thr(34) enhanced tumor cell apoptosis induced by anticancer agents independently of p53 and suppressed tumor growth without toxicity in a breast cancer xenograft model in vivo. These data suggest that Thr(34) phosphorylation critically regulates survivin levels in tumor cells and that sequential ablation of p34(cdc2) kinase activity may remove the survivin viability checkpoint and enhance apoptosis in tumor cells.
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PMID:Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. 1251 2

The call for the discovery of less toxic, more selective, and more effective agents to treat cancer has become more urgent. Inhibition of angiogenesis continues to be one of the main streams in the current cancer drug discovery activity. Insights into tumor angiogenesis biology have led to the identification of a number of molecules, which are important for the progression of these processes. Of particular interest is a group of growth factors including fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor. These growth factors and their corresponding receptor tyrosine kinases have become important targets for inhibition of the proliferation of endothelial cells, the main component of blood vessels. The validated targets for inhibition of angiogenesis also include a family of matrix metalloproteinases and cell adhesion molecules. In the closely related area, protein kinases have emerged as one of the most important targets for drug discovery. Besides growth factor receptor tyrosine kinases, numerous other protein kinases implicated in malignancies have been identified including non-receptor kinases such as Bcl-Abl and Src kinases. In addition, the cell cycle regulators (cyclin-dependent kinases, p21 gene) and apoptosis modulators (Bcl-2 oncoprotein, p53 tumor suppressor gene, survivin protein, etc) have also attracted renewed interest as potential targets for anticancer drug discovery. Other molecular targets include protein farnesyltransferase (FTase), histone deacetylase (HDAC), and telomerase, which have essential roles in cellular signal transduction pathways (FTase, HDAC) and cell life-span (telomerase). This review presents a comprehensive summary and discussion on the most important targets currently attracting a great deal of interest in contemporary anticancer drug design and discovery. Recent advances complementing these targets are also highlighted.
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PMID:Current targets for anticancer drug discovery. 1255 68


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