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)

E-cadherin, the major intercellular adhesion molecule of epithelial cells, is important in determining the architecture of sarcomas, especially those showing epithelioid features. In addition to its role in cell adhesion, beta-catenin, a cadherin undercoat protein, has been shown to function as a downstream transcriptional activator of the Wnt/Wingless signaling pathway. In order to evaluate the significance of the cadherin cell adhesion system and the Wnt/Wingless signaling pathway in the morphogenesis and/or tumorigenesis of synovial sarcoma (a major type of sarcoma with epithelioid features), immunoreactivity for pan-cadherin, E-cadherin, and their undercoat proteins (alpha-, beta-,and gamma-catenins and p120) was evaluated in 15 synovial sarcomas. Immunoreactivity for pan-cadherin, E-cadherin, alpha-catenin, beta-catenin, and p120 was observed in all 15 specimens. Immunoreactivity for pan-cadherin was stronger than that for E-cadherin. Expression of gamma-catenin was detected in ten specimens. Although beta-catenin was observed only at the cell-cell boundaries in four specimens, it was present in the nucleus and cytoplasm and at the cell-cell boundaries in the other 11, suggesting constitutional activation of the Wnt/Wingless signaling pathway in synovial sarcoma. Direct sequencing for exon 3 of the beta-catenin gene, however, revealed no mutations in any of the 15 specimens. In conclusion, other types of cadherin besides E-cadherin, together with cadherin undercoat proteins, may play a role in cell adhesion in synovial sarcoma. Furthermore, mechanisms other than mutation of exon 3 of the beta-catenin gene may activate the Wnt/Wingless signaling pathway in this type of tumor.
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PMID:Expression of cadherins and their undercoat proteins (alpha-, beta-, and gamma-catenins and p120) and accumulation of beta-catenin with no gene mutations in synovial sarcoma. 1121 32

beta-catenin was shown to be a major oncoprotein in colon cancer development. Its oncogenic function as a transcriptional activator is upregulated by mutations in the APC tumor suppressor gene, leading to a constitutive activation of the proliferation-associated genes c-myc and cyclin D. The aim of this study was to demonstrate a role of APC-mutations and dysregulated beta-catenin also for the progression of colorectal cancer, by identifying new target genes of beta-catenin associated with tumor invasion and metastasis. Potential invasion genes regulated by beta-catenin and its DNA binding partner TCF4 were identified by a computer search for the consensus DNA binding sequence in relevant promoter regions. Specific DNA binding was confirmed by gel shift assays. Functional importance of beta-catenin for the activation of identified genes was determined by luciferase reporter assays. The significance was demonstrated by coexpression of nuclear beta-catenin and the identified target genes by immunohistochemistry. Among other invasion genes, we identified the matrix metallo proteinases MMP-7 and MMP-1 activated by beta-catenin in the tumor cells. MMP-7 is an important factor for invasion and metastasis and overexpressed in 75% of colon carcinomas. The significance for human colon cancer development was demonstrated by a correlated overexpression of beta-catenin and the MMPs, beginning in large, severely dysplastic adenomas. Our results explain the high percentage of MMP-7 overexpression in colorectal tumors and the resulting activation of invasive growth. Moreover by identifying dysregulated beta-catenin as a transcriptional activator of MMPs and other invasion factors, we demonstrated an important role of mutated APC not only for early steps but also for the progression of colorectal carcinogenesis.
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PMID:[beta-Catenin induces invasive growth by activating matrix metalloproteinases in colorectal carcinoma]. 1121 38

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator composed of HIF-1alpha and HIF-1beta subunits. Several dozen HIF-1 targets are known, including the gene encoding vascular endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1alpha expression increases as a result of decreased ubiquitination and degradation. The tumor suppressors VHL (von Hippel-Lindau protein) and p53 target HIF-1alpha for ubiquitination such that their inactivation in tumor cells increases the half-life of HIF-1alpha. Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased PTEN activity in prostate cancer cells also increases HIF-1alpha expression by an undefined mechanism. In breast cancer, increased activity of the HER2 (also known as neu) receptor tyrosine kinase is associated with increased tumor grade, chemotherapy resistance, and decreased patient survival. HER2 has also been implicated as an inducer of VEGF expression. Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1alpha protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression, heregulin stimulation does not affect the half-life of HIF-1alpha but instead stimulates HIF-1alpha synthesis in a rapamycin-dependent manner. The 5'-untranslated region of HIF-1alpha mRNA directs heregulin-inducible expression of a heterologous protein. These data provide a molecular basis for VEGF induction and tumor angiogenesis by heregulin-HER2 signaling and establish a novel mechanism for the regulation of HIF-1alpha expression.
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PMID:HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. 1135 7

The p53 tumor-suppressor protein functions as a transcriptional activator, and several p53-inducible genes that play a role in the induction of apoptosis in response to p53 have been described. We have identified a novel gene named PUMA (p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain-containing proteins (PUMA-alpha and PUMA-beta) that are induced in cells following p53 activation. PUMA-alpha and PUMA-beta show similar activities; they bind to Bcl-2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role in mediating p53-induced cell death through the cytochrome c/Apaf-1-dependent pathway.
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PMID:PUMA, a novel proapoptotic gene, is induced by p53. 1146 92

Suppressor of fused (Su(fu)) is a negative regulator of the Hedgehog signaling pathway that controls the nuclear-cytoplasmic distribution of Gli/Ci transcription factors through direct protein-protein interactions. We show here that Su(fu) is present in a complex with the oncogenic transcriptional activator beta-catenin and functions as a negative regulator of T-cell factor (Tcf)-dependent transcription. Overexpression of Su(fu) in SW480 (APC(mut)) colon cancer cells in which beta-catenin protein is stabilized leads to a reduction in nuclear beta-catenin levels and in Tcf-dependent transcription. This effect of Su(fu) overexpression can be blocked by treatment of these cells with leptomycin B, a specific inhibitor of CRM1-mediated nuclear export. Overexpression of Su(fu) suppresses growth of SW480 (APC(mut)) tumor cells in nude mice. These observations indicate that Su(fu) negatively regulates beta-catenin signaling and that CRM-1-mediated nuclear export plays a role in this regulation. Our results also suggest that Su(fu) acts as a tumor suppressor.
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PMID:Suppressor of fused negatively regulates beta-catenin signaling. 1147 86

Renal transplant recipients are prone to numerous benign and malignant skin lesions. Previous work in the authors' laboratory has determined that the human papillomavirus may be the viral aetiology of these skin lesions. The p53 tumor-suppressor gene is the most frequently mutated gene in a wide range of human cancers. Here the authors describe an immunohistochemical study to evaluate the expression of p53 in benign and malignant skin lesions from renal transplant recipients and immunocompetent patients with skin cancer. The effect of p53 mutations on the expression patterns observed were examined by polymerase chain reaction-single strand conformation polymorphism analysis and direct cycle sequencing. The expression of the p53-regulated cyclin-dependant kinase inhibitor p21Waf1/Cip1 and Mdm2 was also examined in p53-positive cells. The expression of p53 in benign and malignant lesions was found to be markedly different. p53 was expressed in only 40% (6/15) of viral warts analyzed. The expression was confined to the basal layer both in the lesion and in adjacent normal skin, and the level of expression was low and only in a small number of cells (<10%). Of the cutaneous squamous cell carcinomas analyzed, 60% (9/15) showed p53 expression. Two different patterns of expression were observed. Basal layer expression in both the invasive tumor and adjacent normal skin was observed in 50% of the p53-positive squamous cell carcinomas; in the remaining 50%, p53 was expressed diffusely throughout the invasive tumor and in the basal layer of adjacent normal skin. The level of expression was high and in a large number of cells. Polymerase chain reaction-single strand conformation polymorphism analysis revealed that only one of the squamous cell carcinomas expressing p53 harbored a p53 mutation and that the accumulated p53 in the remaining tumors was wild type. No Mdm2 or p21Waf1/Cip1 expression was detected in the p53-positive squamous cell carcinomas, indicating that although the accumulated p53 is stable, it does not function effectively as a transcriptional activator. This represents a novel p53 phenotype in cutaneous squamous cell carcinoma. In addition, no correlation was seen between the presence and absence of human papillomavirus and p53 expression.
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PMID:Altered p53 expression in benign and malignant skin lesions from renal transplant recipients and immunocompetent patients with skin cancer: correlation with human papillomaviruses? 1155 22

Inactivating mutations in the adenomatous polyposis coli (APC) gene correlate with progression of colon cancer and familial adenomatous polyposis. The APC tumor suppressor contributes to chromosome segregation and turnover of the oncogenic transcriptional activator beta-catenin, and these activities are impaired by truncating cancer mutations. APC was recently identified as a shuttling protein whose subcellular distribution is regulated by two nuclear localization signals (NLSs) and multiple nuclear export signals (NESs). Here, we show that mutant disease-linked truncated forms of APC, most of which lack the two central NLSs and certain NES sequences, retain nuclear-cytoplasmic shuttling activity. Nuclear export of truncated APC is mediated by a dominant N-terminal NES. Nuclear import of NLS-deficient APC mutants is facilitated by the N-terminal ARM domain. Furthermore, co-expression of the ARM-binding protein, B56 alpha, increased the nuclear localization of mutant and wild-type APC. The minimal B56 alpha-responsive sequence mapped to APC amino acids 302-625. B56 alpha is a regulatory subunit of protein phosphatase 2A; however, its ability to shift APC to the nucleus was independent of phosphatase activity. We conclude that APC nuclear import is regulated by the ARM domain through its interaction with B56 alpha and postulate that APC/B56 alpha complexes target the dephosphorylation of specific proteins within the nucleus.
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PMID:ARM domain-dependent nuclear import of adenomatous polyposis coli protein is stimulated by the B56 alpha subunit of protein phosphatase 2A. 1158 28

The yeast NuA4 complex is a histone H4 and H2A acetyltransferase involved in transcription regulation and essential for cell cycle progression. We identify here a novel subunit of the complex, Yng2p, a plant homeodomain (PHD)-finger protein homologous to human p33/ING1, which has tumor suppressor activity and is essential for p53 function. Mass spectrometry, immunoblotting, and immunoprecipitation experiments confirm the stable stoichiometric association of this protein with purified NuA4. Yeast cells harboring a deletion of the YNG2 gene show severe growth phenotype and have gene-specific transcription defects. NuA4 complex purified from the mutant strain is low in abundance and shows weak histone acetyltransferase activity. We demonstrate conservation of function by the requirement of Yng2p for p53 to function as a transcriptional activator in yeast. Accordingly, p53 interacts with NuA4 in vitro and in vivo, an interaction reminiscent of the p53-ING1 physical link in human cells. The growth defect of Delta yng2 cells can be rescued by the N-terminal part of the protein, lacking the PHD-finger. While Yng2 PHD-finger is not required for p53 interaction, it is necessary for full expression of the p53-responsive gene and other NuA4 target genes. Transcriptional activation by p53 in vivo is associated with targeted NuA4-dependent histone H4 hyperacetylation, while histone H3 acetylation levels remain unchanged. These results emphasize the essential role of the NuA4 complex in the control of cell proliferation through gene-specific transcription regulation. They also suggest that regulation of mammalian cell proliferation by p53-dependent transcriptional activation functions through recruitment of an ING1-containing histone acetyltransferase complex.
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PMID:Role of an ING1 growth regulator in transcriptional activation and targeted histone acetylation by the NuA4 complex. 1160 99

Loss of Dmp1, an Arf transcriptional activator, leads to spontaneous tumorigenesis in mice, causing death from various forms of cancer by two years of age. Retention and expression of the wild-type Dmp1 allele in tumors arising in Dmp1(+/-) mice demonstrate that Dmp1 can be haplo-insufficient for tumor suppression. The mean latency of E(mu)-Myc-induced B-cell lymphomas is halved on a Dmp1(-/-) or Dmp1(+/-) genetic background. Although p53 mutations or Arf deletion normally occur in approximately 50% of E(mu)-Myc-induced lymphomas, Dmp1 loss obviates selection for such mutations, indicating that Dmp1 is a potent genetic modifier of the Arf-p53 pathway in vivo.
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PMID:Dmp1 is haplo-insufficient for tumor suppression and modifies the frequencies of Arf and p53 mutations in Myc-induced lymphomas. 1171 28

The migration-inducing gamma2 chain of laminin-5, one of the best known invasion markers, is strongly overexpressed in disseminating and infiltrating tumor cells at the invasive front of colorectal carcinomas. The same tumor cells show nuclear accumulation of the oncoprotein beta-catenin, which together with T-cell factor-DNA-binding proteins, functions as transcriptional activator of genes involved in tumor progression. Here we show that beta-catenin activates the human laminin-5 gamma2 gene through two T-cell factor-binding elements in a synergistic manner together with hepatocyte growth factor and conclude that laminin-5 gamma2 is another important target gene of nuclear beta-catenin during tumor progression.
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PMID:Expression of the invasion factor laminin gamma2 in colorectal carcinomas is regulated by beta-catenin. 1171 33


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