Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IFN-gamma transduces signals by activating the IFN-gamma receptor-associated Jak-1 and Jak-2 kinases and by inducing tyrosine phosphorylation and activation of the Stat-1 transcriptional activator. We report that IFN-gamma activates a distinct signaling cascade involving the c-cbl protooncogene product, CrkL adapter, and small G protein Rap1. During treatment of NB-4 human cells with IFN-gamma, c-cbl protooncogene product is rapidly phosphorylated on tyrosine and provides a docking site for the src homology 2 domain of CrkL, which also undergoes IFN-gamma-dependent tyrosine phosphorylation. CrkL then regulates activation of the guanine exchange factor C3G, with which it interacts constitutively via its N terminus src homology 3 domain. This results in the IFN-gamma-dependent activation of Rap1, a protein known to exhibit tumor suppressor activity and mediate growth inhibitory responses. In a similar manner, Rap1 is also activated in response to treatment of cells with type I IFNs (IFN-alpha, IFN-beta), which also engage CrkL in their signaling pathways. On the other hand, IFN-gamma does not induce formation of nuclear CrkL-Stat5 DNA-binding complexes, which are induced by IFN-alpha and IFN-beta, indicating that pathways downstream of CrkL are differentially regulated by different IFN subtypes. Taken altogether, our data demonstrate that, in addition to activating the Stat pathway, IFN-gamma activates a distinct signaling cascade that may play an important role in the generation of its growth inhibitory effects on target cells.
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PMID:IFN-gamma activates the C3G/Rap1 signaling pathway. 1065 27

Most colorectal cancers have loss-of-function mutations in the adenomatosis polyposis coli (APC) tumor suppressor gene. This leads to the accumulation of nuclear beta-catenin, which, together with the DNA-binding protein TCF-4, functions as a transcriptional activator. The recently defined target genes c-myc, cyclin D1, and matrilysin are responsible for tumor proliferation or malignant progression and explain the oncogenic potential of nuclear beta-catenin. To investigate its role in early colon carcinogenesis, we analyzed the expression of beta-catenin, its target gene c-myc, and the proliferative activity in 88 colorectal adenomas of varying size and grade of dysplasia. The results revealed i) the most significant correlation of nuclear beta-catenin and c-myc expression was not with the grade of dysplasia but with the size of the colon adenoma; ii) perfect correlation of nuclear beta-catenin and c-myc expression; iii) no significant correlation of adenoma size with the proliferative activity; and iv) no significant correlation of proliferative activity and the nuclear expression of beta-catenin and c-myc. These results imply that APC mutations have additional beta-catenin-independent functions; APC mutations alone are not sufficient for nuclear overexpression of beta-catenin; and nuclear beta-catenin has additional important functions for exceeding a threshold tumor size.
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PMID:Expression of nuclear beta-catenin and c-myc is correlated with tumor size but not with proliferative activity of colorectal adenomas. 1070 3

The tumor suppressor gene p53 is mutated in a large proportion of human cancers. In some cellular conditions like DNA damage, the p53 gene is induced and its gene product is posttranscriptionally activated. p53 works as a transcriptional activator and induces the expression of its downstream target genes. This review will explain why expression of the normal p53 gene leads to tumor growth suppression. The p53 has several biological effects involving cell-cycle arrest, DNA replication and repair, proliferation, apoptosis, angiogenesis inhibition, and cellular stress response. These effects of the p53 result mainly from the activation of expression of a large number of p53-target genes. Here we have focused on the biological functions of the transcriptional targets of p53.
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PMID:The role of p53-target genes in human cancer. 1071 58

During genital human papillomavirus (HPV) infection several cytokines are released, such as interleukin-1 (IL-1), tumor necrosis factoralpha (TNFalpha), IL-6, and IL-8. These cytokines may play a role in the immune surveillance against viral infection. Two of these cytokines, IL-1 and TNFalpha, suppress the transcription of the HPV16 early genes. CAATT/ enhancer binding protein, (C/EBPbeta), which is activated by IL-1 and TNFalpha, has been suggested to act as a mediator of this transcriptional downregulation. C/EBPbeta contains three different translation initiation sites that can lead probably by leaky ribosome scanning to the generation of three isoforms of C/EBPbeta, namely full-length C/EBPbeta, liver enriched transcriptional activator protein (LAP), and liver enriched inhibitory protein (LIP). When transiently expressed in C33A and HeLa cells, the first two C/EBPbeta isoforms activate the HPV16 long control region (LCR). LIP, which acts as an antagonist of C/EBPbeta, represses the HPV16 LCR activity. Our observation that treatment of HeLa cells with IL-1 leads to induction of LIP supports the hypothesis that the LCR downregulation by IL-1 is mediated by LIP.
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PMID:Transcriptional regulation of human papillomavirus type 16 LCR by different C/EBPbeta isoforms. 1082 Apr 87

Although the beneficial effect of cimetidine on survival in cancer has been clinically demonstrated in colorectal cancer patients, the mode of action of cimetidine has not been elucidated. In this report, we have demonstrated for the first time that cimetidine can block the adhesion of a colorectal tumor cell line to the endothelial cell monolayer in cell culture and that it can suppress the metastasis of the tumor cell in a nude mouse model. We also demonstrated that these antimetastasis effects of cimetidine might occur through down-regulation of the cell surface expression of E-selectin on endothelial cells, a ligand for sialyl Lewis antigens on tumor cells. We found that the cimetidine-mediated down-regulation of E-selectin did not involve down-regulation of E-selectin mRNA or blocking of the nuclear translocation of nuclear factor kappaB, a transcriptional activator of E-selectin gene expression. Because two other histamine type 2 receptor antagonists, famotidine and ranitidine, did not show any similar effect, these actions of cimetidine probably do not occur via blocking of the histamine receptor. These observations support the idea that cancer metastasis can be blocked by cimetidine administration through blocking the adhesion of tumor cells to the endothelium when an interaction between E-selectin and sialyl-Lewis antigens plays a role.
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PMID:Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression. 1091 77

beta-Catenin acts as a downstream transcriptional activator of the Wingless-Wnt signaling pathway. The beta-catenin-Tcf complex transactivates the downstream genes that regulate cell proliferation or inhibit apoptosis. The activation of this pathway through stabilization of beta-catenin is caused either by inactivating mutations of adenomatous polyposis coli (APC) tumor suppressor gene or by activating mutations in beta-catenin exon 3. To determine whether the abnormal expression and activating mutations in exon 3 of the beta-catenin gene are implicated in renal cell carcinogenesis, 52 renal cell carcinomas (RCC) were analyzed by immunohistochemistry, polymerase chain reaction-single-strand conformational polymorphism analysis (PCR-SSCP), and direct DNA sequencing. Immunohistochemically, all cases, as well as normal kidneys, showed membranous and/or cytoplasmic staining patterns without nuclear localization. However, the cytoplasmic accumulations of beta-catenin were observed in five (22.7%) of 22 cases of conventional (clear cell) renal carcinoma, but not in papillary or chromophobe renal carcinomas. The beta-catenin mutation was identified in only one case of conventional renal carcinoma and was a single-base missense mutation on codon 61, leading to substitution of glutamine by arginine. In conclusion, this study demonstrates that beta-catenin mutations are a relatively rare event in RCC and that cytoplasmic accumulations of beta-catenin protein are found only in conventional (clear cell) renal carcinomas. These data suggest that the activation of the beta-catenin signaling pathway may partly play a role in the development of conventional RCC.
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PMID:beta-catenin expression and mutational analysis in renal cell carcinomas. 1101 86

Bovine leukemia virus (BLV) Tax protein, a transcriptional activator of viral expression, is essential for viral replication in vivo. Tax is believed to be involved in leukemogenesis because of its second function, immortalization of primary cells in vitro. These activities of Tax can be dissociated on the basis of point mutations within specific regions of the protein. For example, mutation of the phosphorylation sites at serines 106 and 293 abrogates immortalization potential in vitro but maintains transcriptional activity. This type of mutant is thus particularly useful for unraveling the role of Tax immortalization activity during leukemogenesis independently of viral replication. In this report, we describe the biological properties of BLV recombinant proviruses mutated in the Tax phosphorylation sites (BLVTax106+293). Titration of the proviral loads by semiquantitative PCR revealed that the BLV mutants propagated at wild-type levels in vivo. Furthermore, two animals (sheep 480 and 296) infected with BLVTax106+293 developed leukemia or lymphosarcoma after 16 and 36 months, respectively. These periods of time are within the normal range of latencies preceding the onset of pathogenesis induced by wild-type viruses. The phenotype of the mutant-infected cells was characteristic of a B lymphocyte (immunoglobulin M positive) expressing CD11b and CD5 (except at the final stage for the latter marker), a pattern that is typical of wild-type virus-infected target cells. Interestingly, the transformed B lymphocytes from sheep 480 also coexpressed the CD8 marker, a phenotype rarely observed in tumor biopsies from chronic lymphocytic leukemia patients. Finally, direct sequencing of the tax gene demonstrated that the leukemic cells did not harbor revertant proviruses. We conclude that viruses expressing a Tax mutant unable to transform primary cells in culture are still pathogenic in the sheep animal model. Our data thus provide a clear example of the discordant conclusions that can be drawn from in vitro immortalization assays and in vivo experiments. These observations could be of interest for other systems, such as the related human T-cell leukemia virus type 1, which currently lack animal models allowing the study of the leukemogenic process.
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PMID:Discordance between bovine leukemia virus tax immortalization in vitro and oncogenicity in vivo. 1102 16

We have applied engineered transcriptional repressors to specifically inhibit disease gene-activated pathways in oncogenesis. We have demonstrated that synthetic repressors combining PAX3 DNA binding domains with different repression domains, KRAB or SNAG, are able to specifically inhibit malignant growth and suppress tumorigenesis in alveolar rhabdomyosarcoma tumor cells transformed by the translocation-derived chimeric transcriptional activator, PAX3-FKHR. We discuss the potential applications of the engineered repressor strategy that relate to target gene analysis, mechanisms of repression, cell regulation, and possible anti-viral and cancer therapy.
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PMID:Regulating the neoplastic phenotype using engineered transcriptional repressors. 1116 87

Human MDM2 (hMDM2) inhibits transcriptional activation mediated by wild-type p53 and its tumor-derived mutants. We present evidence to show that hMDM2 interacts with the tumor-derived mutants of p53 and inhibits transcriptional activation of the human c-myc promoter mediated by the tumor-derived mutants of p53 through two domains. These two domains of hMDM2 are able to function independent of each other. Interaction with either of the domains is sufficient for inhibition of mutant p53-mediated transactivation. One of these domains is the same as the wild-type p53 interaction domain of hMDM2, whereas a second domain is situated within amino acid 190 and 276 residues and is specific for mutant p53. hMDM2 does not inhibit transcriptional activation mediated by the transcriptional activator VP16, suggesting that the inhibition is not mediated by inactivation of a general transcription factor. The transactivation and the oligomerization domains of mutant p53 are dispensable for its interaction with hMDM2. Thus, both hMDM2 and p53 recognize each other through unique domains. These observations suggest that forms of hMDM2 incapable of interacting with the wild-type p53, and are often expressed in transformed cells, would inhibit mutant p53-mediated transactivation and antagonize the tumorigenic function of mutant p53. This inhibitory function of hMDM2 may account for infrequent co-occurrence of p53 mutation and hMDM2 overexpression in cancer cells. Our results also suggest distinct mechanisms for wild-type and mutant p53-mediated transcriptional activation.
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PMID:The human oncoprotein MDM2 uses distinct strategies to inhibit transcriptional activation mediated by the wild-type p53 and its tumor-derived mutants. 1117 71

In brain, breast, and other common human tumors there is a correlation between expression of the transcriptional activator hypoxia-inducible factor 1 (HIF-1) and tumor grade and vascularization. HIF-1 stimulates angiogenesis by activating transcription of the gene encoding vascular endothelial growth factor (VEGF). HIF-1 is a heterodimer consisting of a constitutively-expressed HIF-1beta subunit and an O2- and growth factor-regulated HIF-1alpha subunit. Recent studies have demonstrated that HIF-1alpha expression is increased in tumor relative to normal tissue by two mechanisms. First, decreased intratumoral O2 concentrations provide a physiological stimulus. Second, genetic alterations that activate oncogene products or inactivate tumor suppressor gene products increase HIF- 1alpha expression and/or HIF-1 transcriptional activity independent of the O2 concentration. Taken together, these recent data suggest that increased HIF-1 activity provides a molecular basis for VEGF-induced angiogenesis and other adaptations of cancer cells to hypoxia that are critical for establishment of a primary tumor and its progression to the lethal phenotype.
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PMID:HIF-1: using two hands to flip the angiogenic switch. 1119 Oct 64


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