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)

Tumor-derived p53 mutants activate transcription from promoters of various growth-related genes. We tested whether this transactivation function of the mutant protein is sufficient to induce tumorigenesis ('gain of function'). Tumor-derived mutant p53-281G transactivates the promoters of human epidermal growth factor receptor (EGFR) and human multiple drug resistance gene (MDR-1). To determine whether the C-terminal domain functions only as an oligomerization domain in mutant p53-mediated transactivation, we have replaced the tetramerization domain of p53 by a heterologous tetramerization domain; although this mutant protein formed tetramers in solution, it failed to transactivate significantly. Therefore, for successful mutant p53-mediated transactivation, sequences near the C-terminus of mutant p53 are required to perform functions in addition to tetramerization. We also demonstrate that co-expression of a deletion mutant of p53 (p53 del 1-293), which retains the p53 oligomerization domain, inhibits this transactivation. p53 del 1-293 co-immunoprecipitates with p53-281G suggesting that hetero-oligomers of p53-281G and p53 del 1-293 are defective in transactivation. We also show that a cell line stably transfected with p53-281G expresses higher levels of endogenous NF-kappaB and proliferating cell nuclear antigen (PCNA) compared to that transfected with vector alone. On co-expression, p53 del 1-293 lowered the levels of NF-kappaB and PCNA in p53-281G-expressing cells. However, on co-expression, p53 del 1-293 did not inhibit the tumorigenicity and colony forming ability of p53-281G expressing cells. Our earlier work showed that a deletion of the C-terminal sequences of p53-281G overlapping the oligomerization domain obliterates 'gain of function'. Taken together, the above information suggests that the C-terminal sequences have some critical role in 'gain of function' in addition to transactivation.
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PMID:Hetero-oligomerization does not compromise 'gain of function' of tumor-derived p53 mutants. 1180 61

Extensive studies indicate that both p53 and multidrug transporters play important roles in chemoresistance. Since the initial reports a decade ago demonstrating a transcriptional dependence of the ABCB1 gene (MDR) promoter by p53, much data have been accumulated. However, despite being the subject of intense study, this p53-MDR relationship remains unclear in human cancers. The data are confounded by variable and contrasting results when considering the in vitro regulation and attempting to draw parallels in tissue specimens. The original model suggested that wild-type p53 downregulates the ABCB1 promoter, whereas mutant p53 increases expression of ABCB1. This review summarizes the data for and against this hypothesis. What emerges from these studies is a complex picture, where data have been obtained in support of this hypothesis, but there are also many circumstances where it is not supported. Taken together, these data suggest that the relationship between p53 and multidrug transporters is conditional. It is dependent on cellular environment, the drug used, and the nature of the p53 mutation.
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PMID:Cancer chemoresistance: the relationship between p53 and multidrug transporters. 1192 May 81

Mutation of p53 has been implicated in progression of classical Wilms tumor (WT) into the anaplastic variant (AWT), drug resistance, and poor prognosis. Because of prognostic similarities, clear cell sarcoma of the kidney (CCSK) has been classified with AWT and other aggressive pediatric renal tumors, apart from congenital mesoblastic nephroma (CMN), which is instead a relatively benign tumor of neonates. Initially, CCSK and CMN were assumed to be ontologically related, but the role of p53 in the pathogenesis of either disease has not been sufficiently evaluated as in AWT. We examined the status of p53 in CMN and CCSK in comparison to AWT by immunohistochemistry and mRNA analysis of p53, the downstream effector p21(WAF-1/CIP-1) ( p21), the multidrug resistance gene MDR-1, a putative target of p53, and the p53-antagonist Mdm-2. Surprisingly, strong p53 nuclear immunoreactivity was found in cultures from two CMN specimens, but not in frozen or fixed tumor tissue from five other CMN specimens, nor in cell lines or tumor tissue from CCSK. Sequence analysis excluded p53 mutations. The size of the p53 mRNA in CMN and CCSK primary tumors excluded gross deletions or rearrangements. Low levels of Mdm-2 mRNA in CCSK and CMN primary tumors and cultures did not support a role for Mdm-2. Absence of MDR-1 mRNA excluded MDR-1 in the drug-resistant phenotype of CCSK. Cisplatin-induced p21 transactivation assays and G(1) cell cycle arrest analyses showed that p21 transactivation and G(1) arrest occurred in both CCSK and CMN cultures, demonstrating integrity of the p53 signal transduction pathway. Absence of p53 functional abnormalities excluded relationships between CCSK and CMN as in AWT, supporting the association of cellular CMN with congenital fibrosarcomas as more recently proposed.
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PMID:Functional and gene expression analysis of the p53 signaling pathway in clear cell sarcoma of the kidney and congenital mesoblastic nephroma. 1200 18

For the treatment of ovarian cancer, gene therapy is increasingly viewed as the fourth therapeutic concept (in addition to surgery, chemotherapy, and irradiation). Many approaches that use viral and nonviral delivery systems have been employed to introduce genes into tumor cells, thus changing their malignant phenotype. The development of tissue-specific promoters has enhanced the specificity of adenoviral transduction, the most commonly used transfer method. Phase I clinical trials (targeting p53, BRCA1, Her2/neu, Bcl-2, MDR, EIA, and HSV-TK genes) have been performed to test the relative safety of different strategies. Further studies are needed to evaluate the effectiveness of these treatments. New studies must evaluate gene therapy alone and in combination with cytostatic regimens because preclinical studies have shown the chemosensitizing effects of several target genes. The increasing knowledge about the genetic background of ovarian cancer will provide many targets for novel gene therapy approaches.
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PMID:Gene therapy of ovarian cancer. 1211 82

Drug resistance, intrinsic or acquired, is a problem for all chemotherapeutic agents. In this review, we examine numerous strategies that have been tested or proposed to reverse drug resistance. Included among these strategies are approaches targeting the apoptosis pathway. Although the process of apoptosis is complex, it provides several potential sites for therapeutic intervention. A variety of targets and approaches are being pursued, including the suppression of proteins inhibiting apoptosis using antisense oligonucleotides (ASOs), and small molecules targeted at proteins that modulate apoptosis. An alternate strategy is based on numerous studies that have documented methylation of critical regions in the genome in human cancers. Consequently, efforts have been directed at re-expressing genes, including genes that affect drug sensitivity, using 5-azacytidine and 2'-deoxy-5-azacytidine (DAC, decitabine) as demethylating agents. While this strategy may be effective as a single modality, success will most likely be achieved if it is used to modulate gene expression in combination with other modalities such as chemotherapy. At a more basic level, attempts have been made to modulate glutathione (GSH) levels. Owing to its reactivity and high intracellular concentrations, GSH has been implicated in resistance to several chemotherapeutic agents. Several approaches designed to deplete intracellular GSH levels have been pursued including the use of buthionine-(S,R)-sulfoxime (BSO), a potent and specific inhibitor of gamma-glutamyl cysteine synthetase (gamma-GCS), the rate-limiting step in the synthesis of GSH, a hammerhead ribozyme against gamma-GCS mRNA to downregulate specifically its levels and targeting cJun expression to reduce GSH levels. Alternate strategies have targeted p53. The frequent occurrence of p53 mutations in human cancer has led to the development of numerous approaches to restore wild-type (wt) p53. The goals of these interventions are to either revert the malignant phenotype or enhance drug sensitivity. The approach most extensively investigated has utilized one of several viral vectors. An alternate approach, the use of small molecules to restore wt function to mutant p53, remains an option. Finally, the conceptually simplest mechanism of resistance is one that reduces intracellular drug accumulation. Such reduction can be effected by a variety of drug efflux pumps, of which the most widely studied is P-glycoprotein (Pgp). The first strategy utilized to inhibit Pgp function relied on the identification of non-chemotherapeutic agents as competitors. Other approaches have included the use of hammerhead ribozymes against the MDR-1 gene and MDR-1-targeted ASOs. Although modulation of drug resistance has not yet been proven to be an effective clinical tool, we have learned an enormous amount about drug resistance. Should we succeed, these pioneering basic and clinical studies will have paved the road for future developments.
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PMID:Strategies for reversing drug resistance. 1457 55

It has been suggested that histologic subtype of ovarian cancer is a factor that determines the chemoresponsiveness of tumor. In this study, we wanted to clarify the prognostic significance of histologic subtype and its correlation to expression of chemoresistance-related proteins (CRPs) in ovarian cancer. A total of 93 stage II-IV ovarian cancers, where the proportion of serous, endometrioid, mucinous, and clear cell subtype was 61.3%, 14.0%, 7.5%, and 17.2%, respectively, were investigated for glutathione S-transferase-pi (GST-pi), MDR (multidrug resistance)-1, and p53 expression using immunohistochemistry. GST-pi expression was detected in 62.4% of the tumors and was not related to histologic subtype of tumor. MDR-1 expression was observed in 12.9% of the tumors tested and was more frequently detected in clear cell adenocarcinomas than other histologic subtypes of tumor (10/ 16 vs. 2 / 77, P < 0.001). P53 expression was found in 49.1% of serous, 53.8% of endometrioid, and 50% of mucinous adenocarcinomas. In contrast, none of 16 clear cell adenocarcinomas showed positive p53 staining. In univariate analysis, no direct correlations were found between CRPs and overall survival. Histology of mucinous/clear cell tumors (P = 0.0063), as well as FIGO stage III/IV (P = 0.0091) and residual tumor >or= 2 cm (P = 0.0045), was found to have independent prognostic value in multivariate analysis. In conclusion, histologic subtype proved to be the significant independent prognostic factor in addition to FIGO stage and residual tumor in stage II-IV ovarian cancer. GST-pi, MDR-1, and p53 expression pattern is closely related to histologic subtype of ovarian cancer, although they are not significant predictors of survival.
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PMID:Multivariate analysis for prognostic significance of histologic subtype, GST-pi, MDR-1, and p53 in stages II-IV ovarian cancer. 1467 14

By the use of high-resolution two-dimensional gel electrophoresis and computerized image analysis we investigated and compared the expression of cellular proteins from p53 positive (+/+) mouse thymocytes, p53-/- thymocytes before neoplastic transformation, and from cell lines derived from two spontaneous p53-/- thymic lymphomas, SM5 and SM7. A total of around 1500 proteins were detected on individual gels. Only changes in protein expression by a factor of 2 or more were considered. In the thymic lymphoma cells 3-5% of the proteins were found to be differentially regulated when compared with the protein expression in p53+/+ and p53-/- thymocytes. Only a minority (13 proteins) of the quantitatively changed proteins were common for the two thymic lymphoma cell lines, suggesting that the p53 deficiency mainly results in genetic dysfunctions which are individual for a given tumor. Two of the detected proteins increased their expression levels by more than 10 times from the p53+/+ to the p53-/- thymocytes and these high expression levels were also found in thymic lymphomas. The two proteins were identified by mass spectrometry as acidic ribosomal phosphoprotein P0 and a 33-kDa protein with a primary structure containing motifs of the glyoxalase-bleomycin resistance protein family (MDR) as deduced from the cDNA.
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PMID:Changes in protein expression in p53 deleted spontaneous thymic lymphomas. 1505 93

Caveolin-1 is an essential structural constituent of caveolae that has been implicated in mitogenic signaling and oncogenesis. Utilizing MCF-7 human breast cancer cells, stably transfected with caveolin-1 (MCF-7/Cav1), we previously demonstrated that caveolin-1 expression decreases MCF-7 cell proliferation and colony formation in soft agar. However, the loss of anchorage-independent growth is associated with inhibition of anoikis, as MCF-7/Cav1 cells exhibit increased survival after detachment. Herein we show that this phenotype is associated with suppression of detachment-induced activation of p53 and of the consequent induction of cyclin-dependent kinase inhibitor p21(WAF1/Cip1). In contrast, activation of p53 and p21(WAF1/Cip1) induced by doxorubicin in MCF-7/Cav1 cells remains largely unaffected. The phenotypic changes observed in MCF-7/Cav1 cells are not accompanied by changes in caspase-6, -7, -8 and -9 and cannot be explained by changes in Bid and Bcl-2 expression. However, MCF-7/Cav1 cells exhibit a constitutively phosphorylated Akt kinase and at least one phosphorylated high molecular weight putative Akt substrate which we designated pp340. In addition, MCF-7/Cav1 cells exhibit elevated expression of insulin-like growth factor-I (IGF-I) receptor expression and increased IGF-I signaling to Erk1/2 and to Akt, as well as IGF-I-induced stimulation of pp340 phosphorylation. The addition of IGF-I to the medium rescues the parental MCF-7 cells from anoikis, indicating that IGF-1 can act as a survival factor for suspended MCF-7 cells. Finally, the levels of caveolin-1 are dramatically elevated in a time-dependent manner upon detachment of anoikis-resistant MCF-7/Cav1 cells and HT-29-MDR human multidrug resistant colon cancer cells. We conclude that expression of caveolin-1 in human breast cancer cells enhances matrix-independent cell survival that is mediated by upregulation of IGF-I receptor expression and signaling.
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PMID:Caveolin-1 inhibits cell detachment-induced p53 activation and anoikis by upregulation of insulin-like growth factor-I receptors and signaling. 1559 98

The relationship between breast cancer-associated fatty acid synthase (FAS; oncogenic antigen-519) and chemotherapy-induced cell damage has not been studied. We examined the ability of C75, a synthetic slow-binding inhibitor of FAS activity, to modulate the cytotoxic activity of the microtubule-interfering agent Taxol (paclitaxel) in SK-Br3, MDA-MB-231, MCF-7 and multidrug-resistant MDR-1 (P-Glycoprotein)-overexpressing MCF-7/AdrR breast cancer cells. When the combination of C75 with Taxol in either concurrent (C75 + Taxol 24 hr) or sequential (C75 24 hr --> Taxol 24 hr) schedules were tested for synergism, addition or antagonism using the isobologram and the median-effect plot analyses, co-exposure of C75 and Taxol mostly demonstrated synergistic effects, whereas sequential exposure to C75 followed by Taxol mainly showed additive or antagonistic interactions. Because the nature of the cytotoxic interactions was definitely schedule-dependent in MCF-7 cells, we next evaluated the effects of C75 on Taxol-induced apoptosis as well as Taxol-activated cell death and cell survival-signaling pathways in this breast cancer cell model. An ELISA for histone-associated DNA fragments demonstrated that C75 and Taxol co-exposure caused a synergistic enhancement of apoptotic cell death, whereas C75 pre-treatment did not enhance the apoptosis-inducing activity of Taxol. Co-exposure to C75 and Taxol induced a remarkable nuclear accumulation of activated p38 mitogen-activated protein kinase (p38 MAPK), which was accompanied by a synergistic nuclear accumulation of the p53 tumor-suppressor protein that was phosphorylated at Ser46, a p38 MAPK-regulated pro-apoptotic modification of p53. As single agents, FAS blocker C75 and Taxol induced a significant stimulation of the proliferation and cell survival mitogen-activated protein kinase extracellular signal-regulated kinase (ERK1/ERK2 MAPK) activity, whereas, in combination, they interfered with ERK1/ERK2 activation. Moreover, the combined treatment of C75 and Taxol inactivated the anti-apoptotic AKT (protein kinase B) kinase more than either agent alone, as evidenced by a synergistic down-regulation of AKT phosphorylation at its activating site Ser(473) without affecting AKT protein levels. To rule out a role for non-FAS C75-mediated effects, we finally used the potent and highly sequence-specific mechanism of RNA interference (RNAi) to block FAS-dependent signaling. Importantly, SK-Br3 and multi-drug resistant MCF-7/AdrR cells transiently transfected with sequence-specific double-stranded RNA oligonucleotides targeting FAS gene demonstrated hypersensitivity to Taxol-induced apoptotic cell death. Our findings establish for the first time that FAS blockade augments the cytotoxicity of anti-mitotic drug Taxol against breast cancer cells and that this chemosensitizing effect is schedule-dependent. We suggest that the alternate activation of both the pro-apoptotic p38 MAPK-p53 signaling and the cytoprotective MEK1/2 --> ERK1/2 cascade, as well as the inactivation of the anti-apoptotic AKT activity may explain, at least in part, the sequence-dependent enhancement of Taxol-induced cytotoxicity and apoptosis that follows inhibition of FAS activity in breast cancer cells. If chemically stable FAS inhibitors demonstrate systemic anticancer effects of FAS inhibition in vivo, these findings may render FAS as a valuable molecular target to enhance the efficacy of taxanes-based chemotherapy in human breast cancer.
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PMID:Pharmacological and small interference RNA-mediated inhibition of breast cancer-associated fatty acid synthase (oncogenic antigen-519) synergistically enhances Taxol (paclitaxel)-induced cytotoxicity. 1565

Progress in the treatment of colon cancer depends on the development of target-based molecules built on an improved understanding of the molecular biology of the disease. Defining end points for chemotherapy resistance is needed as drug resistance develops quickly and patients demonstrate variation in response to chemotherapy. Many techniques that measure a marker's preponderance have been developed including biochemical, immunohistochemical, genomics, proteomics or a combination thereof. However, standardization of these techniques that measure either genes or their protein products is urgently needed. This article reviews several markers (TS,TP, DPD, FT, EGFR, VEGF, CD44v6, TRAIL, microsatellite instability, allelic deletions, oncogenes and suppressor genes [c-myc, Ki-Ras, p53, p21, Topo I, Topo IIalpha, Fos, hMLH1, Bcl-2/Bax and MDR1], MDR-related proteins [Pgp, MRP and LRP], genomic polymorphisms [XPD, ERCC1, GSTP1 and TS 3 -UTR] and COX-;2) that influence DNA metabolism, DNA damage, programmed cell death, the immune or vascular system, or lead to mutations. When combined together and tested by newly developed genomic and proteomic approaches, many of these markers provide a more sensitive indicative predictor of response than when evaluated separately or by older biochemical, immunohistologic or morphologic methods. A global approach involving the simultaneous testing of several predictive multimarkers will provide critical information for improving chemotherapy to alleviate suffering from this disease.
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PMID:Molecular markers that predict response to colon cancer therapy. 1593 13


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