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

The p53 tumour suppressor gene is the most widely mutated gene in human tumorigenesis. p53 encodes a transcriptional activator whose targets may include genes that regulate genomic stability, the cellular response to DNA damage, and cell-cycle progression. Introduction of wild-type p53 into cell lines that have lost endogenous p53 function can cause growth arrest or induce a process of cell death known as apoptosis. During normal development, self-reactive thymocytes undergo negative selection by apoptosis, which can also be induced in immature thymocytes by other stimuli, including exposure to glucocorticoids and ionizing radiation. Although normal negative selection involves signalling through the T-cell receptor, the induction of apoptosis by other stimuli is poorly understood. We have investigated the requirement for p53 during apoptosis in mouse thymocytes. We report here that immature thymocytes lacking p53 die normally when exposed to compounds that may mimic T-cell receptor engagement and to glucocorticoids but are resistant to the lethal effects of ionizing radiation. These results demonstrate that p53 is required for radiation-induced cell death in the thymus but is not necessary for all forms of apoptosis.
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PMID:p53 is required for radiation-induced apoptosis in mouse thymocytes. 847 14

Pediatric alveolar rhabdomyosarcoma is characterized by a chromosomal translocation that fuses parts of the PAX3 and FKHR genes. PAX3 codes for a transcriptional regulator that controls developmental programs, and FKHR codes for a forkhead-winged helix protein, also a likely transcription factor. The PAX3-FKHR fusion product retains the DNA binding domains of the PAX3 protein and the putative activator domain of the FKHR protein. The PAX3-FKHR protein has been shown to function as a transcriptional activator. Using the RCAS retroviral vector, we have introduced the PAX3-FKHR gene into chicken embryo fibroblasts. Expression of the PAX3-FKHR protein in these cells leads to transformation: the cells become enlarged, grow tightly packed and in multiple layers, and acquire the ability for anchorage-independent growth. This cellular transformation in vitro will facilitate studies on the mechanism of PAX3-FKHR-induced oncogenesis.
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PMID:The hybrid PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma transforms fibroblasts in culture. 879 Apr 12

The A-myb gene is a transcription factor that shares structural and functional similarities with the v-myb oncogene. To date, v-myb is the only myb gene directly implicated in tumorigenesis, a property attributed to its transactivating ability. Recent studies have demonstrated that A-myb, like v-myb, is a potent transcriptional activator, raising the possibility that A-myb may also participate in oncogenesis. To test this hypothesis, we generated fusion constructs that contained the human A-myb cDNA under control of the mouse metallothionein promoter and the mouse mammary tumor virus long terminal repeat. These constructs were inserted into the germ line of mice, and the functional consequences of ectopic A-myb expression were examined. Although transgene expression was detected in a wide range of tissues, abnormalities were confined primarily to hematopoietic tissues. After a 9-month latency, A-myb transgenic mice developed hyperplasia of the spleen and lymph nodes. Enlarged tissues contained a polyclonally expanded B lymphocyte population that expressed a germinal center-cell phenotype. Transgenic B lymphocytes showed increased DNA synthesis in response to low dose mitogen stimulation, suggesting that A-myb may contribute to hyperplasia by increasing the rate of B cell proliferation.
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PMID:Ectopic expression of A-myb in transgenic mice causes follicular hyperplasia and enhanced B lymphocyte proliferation. 909 77

Growth factors of the transforming growth factor-beta (TGF-beta) family inhibit the proliferation of epithelial, endothelial, and hematopoietic cells, and stimulate the synthesis of extracellular matrix components. TGF-beta s are secreted from cells in high-molecular-mass protein complexes that are composed of three proteins, the mature TGF-beta-dimer, the TGF-beta propeptide dimer, or latency-associated protein (LAP), and the latent TGF-beta binding protein (LTBP). Mature TGF-beta is cleaved from its propeptide during secretion, but the proteins remain associated by noncovalent interactions. LTBP is required for efficient secretion and processing of latent TGF-beta and it binds to LAP via disulfide bond(s). LTBP is a component of extracellular matrix microfibrils, and it targets the latent TGF-beta complex to the extracellular matrix. TGF-beta signaling is initiated by proteolytic cleavage of LTBP that results in the release of the latent TGF-beta complex from the extracellular matrix. TGF-beta is activated by dissociation of LAP from the mature TGF-beta. Subsequent signaling involves binding of active TGF-beta to its type II cell surface receptors, which phosphorylate and activate type I TGF-beta receptors. Type I receptors, in turn, phosphorylate cytoplasmic transcriptional activator proteins Smad2 and Smad3, inducing their translocation to the nucleus. Recent evidence suggests that acquisition of resistance to TGF-beta growth inhibition plays a major role in the progression of epithelial and hematopoietic cell malignancies. The role of secretion of TGF-beta in tumorigenesis is more complex. The secretion of TGF-beta s by tumor cells may contribute to autocrine growth inhibition, but on the other hand, it may also promote invasion, metastasis, angiogenesis, and even immunosuppression. Tumor cells may also fail to deposit LTBP:TGF-beta complexes to the extracellular matrix. The elucidation of the mechanisms of the release of TGF-beta from the matrix and its subsequent activation aids the understanding of the pathophysiologic roles of TGF-beta in malignant growth, and allows the development of therapeutic agents that regulate the activity of TGF-beta.
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PMID:Extracellular matrix-associated transforming growth factor-beta: role in cancer cell growth and invasion. 970 8

The 2;13 chromosomal translocation in alveolar rhabdomyosarcoma generates the chimeric protein PAX3-FKHR, which is a powerful transcriptional activator. We hypothesize that PAX3-FKHR regulates downstream effector genes involved in rhabdomyosarcoma tumorigenesis. We evaluated alterations in expression of MET and neural cell adhesion molecule that were proposed previously as downstream targets of wild-type PAX3. We used a myogenic tumor cell culture system and rhabdomyosarcoma tumor specimens to assess candidate gene expression in relationship to various PAX3-FKHR expression levels. We demonstrate that the expression of MET, but not neural cell adhesion molecule, correlates significantly with PAX3-FKHR expression. These findings indicate that MET, which encodes a receptor involved in growth and motility signaling, is a downstream target of PAX3-FKHR in alveolar rhabdomyosarcoma.
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PMID:Up-regulation of MET but not neural cell adhesion molecule expression by the PAX3-FKHR fusion protein in alveolar rhabdomyosarcoma. 972 57

Complex cellular responses are often coordinated by a genetic regulatory network in which a given transcription factor controls the expression of a diverse set of target genes. Interferon regulatory factor (IRF)-1 and IRF-2 have originally been identified as a transcriptional activator and repressor, respectively, of the interferon-beta (IFN-beta) as well as of IFN-inducible genes. However, these factors have since been shown to modulate not only the cellular response to IFNs, but also cell growth, susceptibility to transformation by oncogenes, induction of apoptosis, and development of the T cell immune response. Furthermore, the evidence suggests that deletion and/or inactivation of the IRF-1 gene may be a critical step in the development of some human hematopoietic neoplasms. Subsequently, these factors have been shown to constitute a family of transcription factors, termed the IRF-family. Recent studies indicate that other IRF family members also involve the regulation of the IFN system and cell transformation. The IRF-family may be examples of transcription factors which can selectively modulate several sets of genes depending on the cell type and/or nature of the cellular stimuli, so as to evoke host defense mechanisms against infection and oncogenesis.
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PMID:The role of interferon regulatory factors in the interferon system and cell growth control. 986 86

The interaction between beta-catenin and LEF-1/TCF transcription factors plays a pivotal role in the Wnt-1 signaling pathway. The level of beta-catenin is regulated by partner proteins, including glycogen synthase kinase-3beta (GSK-3beta) and the adenomatous polyposis coli (APC) tumor suppressor protein. Genetic defects in APC are responsible for a heritable predisposition to colon cancer. APC protein and GSK-3beta bind beta-catenin, retain it in the cytoplasm, and facilitate the proteolytic degradation of beta-catenin. Abrogation of this negative regulation allows beta-catenin to translocate to the nucleus and to form a transcriptional activator complex with the DNA-binding protein lymphoid-enhancing factor 1 (LEF-1). This complex is thought to be involved in tumorigenesis. Here we show that covalent linkage of LEF-1 to beta-catenin and to transcriptional activation domains derived from the estrogen receptor or the herpes simplex virus protein VP16 generates transcriptional regulators that induce oncogenic transformation of chicken embryo fibroblasts. The chimeras between LEF-1 and beta-catenin or VP16 are constitutively active, whereas fusions of LEF-1 to the estrogen receptor are regulatable by estrogen. These experiments document the oncogenicity of transactivating LEF-1 and show that the transactivation domain normally provided by beta-catenin can be replaced by heterologous activation domains. These results suggest that the transactivating function of the LEF-1/beta-catenin complex is critical for tumorigenesis and that this complex transforms cells by activating specific LEF-1 target genes.
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PMID:Nuclear endpoint of Wnt signaling: neoplastic transformation induced by transactivating lymphoid-enhancing factor 1. 987 85

Interferon regulatory factor-1 (IRF-1) is a transcriptional activator of genes induced by a variety of cytokines and growth factors. Defects in IRF-1 occur frequently in human cancers and may contribute to tumorigenesis. The IRF family of transcription factors share invariant tryptophan residues that have been proposed to function by orienting the DNA contacting residues of IRF-1 with the DNA core sequence of the IRF element. Here we describe a point mutation in IRF-1 that converts the tryptophan at codon 11 to arginine (W11R). The IRF-1 (W11R) mutation abolishes IRF-1 DNA binding and transactivating activities demonstrating the critical role of this invariant tryptophan in IRF-1 function.
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PMID:Interferon regulatory factor 1 tryptophan 11 to arginine point mutation abolishes DNA binding. 1039 27

p53 has a key role in the negative regulation of cell proliferation, in the maintenance of genomic stability, and in the suppression of transformation and tumorigenesis. To identify novel regulators of p53, we undertook two functional screens to isolate genes which bypassed either p53-mediated growth arrest or apoptosis. In both screens, we isolated cDNAs encoding macrophage migration inhibitory factor (MIF), a cytokine that was shown previously to exert both local and systemic proinflammatory activities. Treatment with MIF overcame p53 activity in three different biological assays, and suppressed its activity as a transcriptional activator. The observation that a proinflammatory cytokine, MIF, is capable of functionally inactivating a tumor suppressor, p53, may provide a link between inflammation and tumorigenesis.
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PMID:A proinflammatory cytokine inhibits p53 tumor suppressor activity. 1056 11

Prostate cancer, the most frequent solid cancer in older men, is a leading cause of cancer deaths. Although proliferation and differentiation of normal prostate epithelia and the initial growth of prostate cancer cells are androgen-dependent, prostate cancers ultimately become androgen-independent and refractory to hormone therapy. The prostate-specific antigen (PSA) gene has been widely used as a diagnostic indicator for androgen-dependent and -independent prostate cancer. Androgen-induced and prostate epithelium-specific PSA expression is regulated by a proximal promoter and an upstream enhancer via several androgen receptor binding sites. However, little progress has been made in identifying androgen-independent regulatory elements involved in PSA gene regulation. We report the isolation of a novel, prostate epithelium-specific Ets transcription factor, PDEF (prostate-derived Ets factor), that among the Ets family uniquely prefers binding to a GGAT rather than a GGAA core. PDEF acts as an androgen-independent transcriptional activator of the PSA promoter. PDEF also directly interacts with the DNA binding domain of androgen receptor and enhances androgen-mediated activation of the PSA promoter. Our results, as well as the critical roles of other Ets factors in cellular differentiation and tumorigenesis, strongly suggest that PDEF is an important regulator of prostate gland and/or prostate cancer development.
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PMID:PDEF, a novel prostate epithelium-specific ets transcription factor, interacts with the androgen receptor and activates prostate-specific antigen gene expression. 1062 66


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