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)

The immunosuppressants cyclosporin and FK506 block the calcium-dependent signal-transduction pathway emanating from the T-cell receptor, thereby inhibiting the activation of helper T cells. Using these drugs as probes, chemists and biologists have uncovered several intracellular signaling molecules bridging the generation of second-messenger Ca2+ ion and the transcriptional activation of IL-2, among which are calmodulin, calcineurin and the nuclear factor of activated T cells (NF-AT). Hence, Ca2+ binds to calmodulin, leading to the binding of calmodulin to calcineurin; the activated calcineurin, in turn, may dephosphorylate the cytoplasmic subunit of NF-AT, resulting in its translocation from the cytoplasm into the nucleus to form a competent transcriptional activator. As described by Jun Liu these drugs manifest their effects in an unprecedented fashion. They do not directly intercept intracellular signaling molecules. Instead, they form tight complexes with two different classes of abundant cytosolic receptors called immunophilins upon entering the cell, and consequently inhibit their peptidyl prolyl cis-trans isomerase activities. The two structurally distinct immunophilin-drug complexes bind to, and inhibit, the phosphatase activity of calcineurin.
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PMID:FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. 769 Oct 65

The immunosuppressants ciclosporin and FK506 block the Ca(2+)-dependent signal-transduction pathway emanating from the T-cell receptor, thereby inhibiting the activation of helper T cells. Using these drugs as probes, chemists and biologists have uncovered several intracellular signalling molecules bridging the generation of second-messenger Ca2+ ions and the transcriptional activation of IL-2, among which are calmodulin, calcineurin and the nuclear factor of activated T cells (NF-AT). Hence, Ca2+ binds to calmodulin, leading to the binding of calmodulin to calcineurin; the activated calcineurin, in turn, may dephosphorylate the cytoplasmic subunit of NF-AT, resulting in its translocation from the cytoplasm into the nucleus to form a competent transcriptional activator. As described by Jun Liu, these drugs manifest their effects in an unprecedented fashion. They do not directly intercept intracellular signalling molecules. Instead, they form tight complexes with two different classes of abundant cytosolic receptors called immunophilins upon entering the cell, and consequently inhibit their peptidyl prolyl cis-trans isomerase activities. The two structurally distinct immunophilin-drug complexes bind to, and inhibit, the phosphatase activity of calcineurin.
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PMID:FK506 and ciclosporin: molecular probes for studying intracellular signal transduction. 769 52

The transcript for the high-affinity Ca2+/calmodulin-binding protein calspermin is generated from the gene encoding Ca2+/calmodulin-dependent protein kinase IV only in postmeiotic germ cells during spermatogenesis. We demonstrate that this testis-specific calspermin transcript can be produced in heterologous cells by utilization of a promoter located in an intron of the calmodulin (CaM) kinase IV gene. Critical motifs within this promoter are two cyclic AMP response element (CRE)-like sequences located about -70 and -50 bp upstream of the transcriptional initiation site. Both CRE motifs are footprinted by the authentic testis-specific transcriptional activator CREM tau or by CREM tau present in adult testis nuclear extract. Whereas a 2.1-kb DNA fragment containing the calspermin promoter is inactive when transfected into NIH 3T3 cells, activity can be restored by cotransfection of CREM tau and protein kinase A or CaM kinase IV but not CaM kinase II alpha. Restoration of activity is greatly reduced by mutation of the two CRE motifs. Since CRE-like motifs have been identified in many genes uniquely expressed in postmeiotic germ cells, which contain abundant CREM tau protein, we suggest that CREM tau may function as one transcription factor responsible for the expression of postmeiotic germ cell-specific genes.
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PMID:Calspermin gene transcription is regulated by two cyclic AMP response elements contained in an alternative promoter in the calmodulin kinase IV gene. 779 65

Primary B cells are induced to proliferate by cross-linking surface immunoglobulin or by its pharmacological equivalent, phorbol ester and calcium ionophore. However, nuclear responses that have been studied in activated B cells are typically inducible with phorbol esters alone. We show that a factor, indistinguishable from the nuclear factor of activated T cells (NF-AT), is induced in B cells in response to anti-immunoglobulin signals or the combined action of phorbol ester and ionomycin, but not in response to either reagent alone. The signals necessary for NF-AT induction in B cells, therefore, closely parallel those required to induce B cell proliferation. Transfection analysis shows that B cell NF-AT is a transcriptional activator. Furthermore, NF-AT induction in splenic cells is suppressed by cyclosporin A, suggesting a mechanism by which immunosuppressive agents act on the B cell compartment. We propose that NF-AT should be considered more generally as a nuclear factor of activated lymphoid cells.
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PMID:Cyclosporin-A sensitive induction of NF-AT in murine B cells. 788 7

The mammalian transcriptional activator CREB binds as a dimer to a broad spectrum of inducible promoters. CREB activity is modulated by several signalling agents (protein kinase A [PKA], Ca2+, and transforming growth factor beta) and via functional interactions with cell-specific transcription factors. In addition, CREB can activate transcription constitutively and repress the activity of several other transcriptional activators. The mechanisms that allow CREB to act in such a malleable manner and the role that CREB dimerization might play in this are poorly understood. To probe the latter issue, we have created monomeric forms of CREB by fusing CREB to the DNA-binding domain of a protein (B-cell specific activator protein [BSAP]) that binds to DNA as a monomer. Remarkably, monomeric CREB acts as a potent, constitutive activator under conditions in which native CREB is inducible by PKA. Thus, CREB contains constitutive activation regions that are unable to function in native CREB. Two glutamine-rich domains that are important for native, PKA-inducible CREB activity are required for the constitutive activity of monomeric CREB. In contrast, two elements within the kinase-inducible domain of CREB are dispensable for constitutive activity. We discuss our results in relation to inducible and constitutive CREB activity and the potential modes of action of other activators that directly interact with CREB.
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PMID:A monomeric derivative of the cellular transcription factor CREB functions as a constitutive activator. 793 35

We have analyzed the effect of antibodies (Abs) directed against major histocompatibility complex (MHC) class II Abs on the proliferation of Theileria parva-infected (Tpi) T cells. Anti-MHC class II Abs exert a direct effect on Tpi T cells causing an acute block in their proliferation. The inhibition does not involve apoptosis and is also entirely reversible. The rapid arrest of DNA synthesis caused by anti-MHC class II Abs is not due to interference with the state of activation of the T cells since the transcriptional activator NF-kappa B remains activated in arrested cells. In addition, interleukin 2 (IL-2), IL-2R, and c-myc gene expression are also unaffected. By analyzing the cell-cycle phase distribution of inhibited cells, it could be shown that cells in all phases of the cell cycle are inhibited. The signal transduction pathway that results in inhibition was shown to be independent of protein kinase C and extracellular Ca2+. Tyrosine kinase inhibitors, however, partly reduced the level of inhibition and, conversely, phosphatase inhibitors enhanced it. The possible relevance of this phenomenon in other systems is discussed.
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PMID:Antibodies against major histocompatibility complex class II antigens directly inhibit the growth of T cells infected with Theileria parva without affecting their state of activation. 835 52

GABAB receptors affect short-term signalling in various cell types. However, nothing is known about possible long-term effects on transcription. To analyse such effects in the CNS, we studied GABAB receptor-mediated gene regulation in primary cultures of cerebellar granule neurons. Transcription was followed using a chloramphenicol acetyl transferase reporter gene driven by the minimal cyclic AMP-responsive element (TGACGTCA). Transcription was stimulated by activation of both the cyclic AMP (forskolin: 5 x 10(-6) M) and the Ca2+ dependent (KCl: 30 mM) pathways (-)-Baclofen (10(-6) M to 10(-4) M), a specific GABAB receptor agonist, reduced by 50-70% the transcriptional stimulation evoked by both forskolin and KCl, whereas isoguvacine, a GABAA receptor agonist, was without effect. Moreover, the GABAB antagonist CGP 35348 abrogated the inhibitory effects of both GABA and baclofen, indicating that GABAB receptors were specifically implicated in this response. Measurements of cyclic AMP levels suggested that (-) baclofen inhibits forskolin-initiated transcription by reducing cyclic AMP production. Direct transcriptional activation, via the cyclic AMP pathway, by overexpression of the catalytic subunit of the cyclic AMP-dependent protein kinase, was not significantly altered by (-) baclofen. This indicates again that (-) baclofen-dependent inhibitory mechanisms operate upstream of cyclic AMP-dependent protein kinase at the level of second messenger formation. Further, we used a yeast transcriptional activator GAL4-cyclic AMP-responsive element binding protein to analyse whether GABAB receptor-mediated inhibition of cyclic AMP-responsive element transcription implicated the transacting factor cyclic AMP-responsive element binding protein. We show that the negative effects of (-) baclofen implicate this transcription factor and this holds good for both the forskolin and KCl-stimulated pathways. The results indicate that GABAB receptors negatively regulate cyclic AMP-responsive element binding protein-mediated transcription in the CNS.
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PMID:GABAB receptors negatively regulate transcription in cerebellar granular neurons through cyclic AMP responsive element binding protein-dependent mechanisms. 884 50

Two ets family members, namely erg and Fli-1 are fused with two EWS family members namely EWS and TLS/FUS as a result of chromosome translocation in human solid tumors and leukemias. EWS-erg and EWS-Fli-1, which are involved in greater than 95% of Ewing family of tumors, were shown to function as transcriptional activators. TLS/FUS-erg, which is involved in human myeloid leukemias also functions as a transcriptional activator. Expression of these fusion proteins (EWS-erg and EWS-Fli-1) are shown to be essential for maintaining the oncogenic and tumorigenic properties of tumor cells. Cancer is thought to be caused not only by uncontrolled cell proliferation but also by deregulation of programmed cell death. Therefore, we have studied the role of normal (Fli-1 and erg) and aberrant fusion proteins (EWS-erg, EWS-Fli-1 and TLS/FUS-erg) in apoptosis. We have found that expression of normal (Fli-1 and erg) and aberrant fusion proteins inhibit the apoptosis of NIH3T3 cells induced by either serum deprivation or by treatment with calcium ionophore. We have also observed similar suppression of apoptosis in Ewing's sarcoma cells expressing EWS-Fli-1 and EWS-erg proteins suggesting that these fusion proteins may be responsible for the decreased ability of these tumor cells to undergo apoptosis. Inhibition of the expression of these aberrant fusion proteins by antisense RNA technique resulted in increased susceptibility to apoptosis leading to the death of tumor cells. Therefore, our results suggest that one can use therapeutic agents which can down regulate the expression of fusion proteins in combination with chemotherapeutic agents as an effective treatment for these human solid tumors and leukemias.
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PMID:Inhibition of apoptosis by normal and aberrant Fli-1 and erg proteins involved in human solid tumors and leukemias. 917 86

Pseudomonas aeruginosa is an opportunistic pathogen and a leading cause of hospital-acquired pneumonia. We identified a 73kDa protein, designated Pseudomonas exoprotein A (PepA), that was secreted by P. aeruginosa strain PA103. PepA was necessary for in vitro killing of epithelial cells as well as virulence in a mouse model of acute pneumonia. Several properties of PepA suggested that it was secreted by a type III system. Secretion occurred without cleavage of a signal peptide and in low-calcium environments in the presence of a divalent cation chelator, as is the case for characterized P. aeruginosa type III secreted proteins. Secretion of PepA was absent from isogenic mutants with defective type III pathways. Finally, amino-terminal peptide sequence analysis indicated that the amino-terminal five residues of PepA were identical to those of ExoS and ExoT, two type III secreted proteins of P. aeruginosa. After secretion, PepA underwent cleavage at two sites, each with the sequence A-X-K-S, suggesting that the cleavage may be caused by a protease. The gene encoding PepA, designated pepA, was cloned and sequenced, and comparisons with the genetic database using BLAST alignments indicated that the nucleotide sequence of pepA and the inferred protein sequence of PepA had no homology to known sequences. A nucleotide sequence identical to the consensus element for binding of ExsA, a transcriptional activator of P. aeruginosa type III secretion genes, was located 84 bp 5' of the translational start codon. Analysis of transposon insertion mutants indicated that the carboxy terminus was required for cytotoxicity. Examination of respiratory clinical isolates demonstrated that pepA was a variable trait and probably acquired by horizontal transmission. Consistent with this hypothesis was the identification of a putative insertion element 94 bp 5' of the PepA translational start site. Analysis of G + C content of the PepA coding sequence and the adjacent insertion element suggested that they were acquired together from a different species. In summary, PepA is a secreted protein of P. aeruginosa that is necessary for epithelial cell cytotoxicity in vitro and virulence in a mouse model of pneumonia.
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PMID:PepA, a secreted protein of Pseudomonas aeruginosa, is necessary for cytotoxicity and virulence. 951 6

Yeast cells deficient in the transcriptional activator Imp2p are viable, but display marked hypersensitivity to a variety of oxidative agents. We now report that imp2 null mutants are also extremely sensitive to elevated levels of the monovalent ions, Na+ and Li+, as well as to the divalent ions Ca2+, Mn2+, Zn2+, and Cu2+, but not to Cd2+, Mg2+, Co2+, Ni2+, and Fe2+, as compared to the parent strain. We next searched for multicopy suppressor genes that would allow the imp2Delta mutant to grow under high salt conditions. Two genes that independently restored normal salt-resistance to the imp2Delta mutant, ENA1 and HAL3, were isolated. ENA1 encodes a P-type ion pump involved in monovalent ion efflux from the cell, while HAL3 encodes a protein required for activating the expression of Ena1p. Neither ENA1 nor HAL3 gene expression was positively regulated by Imp2p. Moreover, the imp2 ena1 double mutant was exquisitely sensitive to Na+/Li+ cations, as compared to either single mutant, implying that Imp2p mediates Na+/Li+ cation homeostasis independently of Ena1p.
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PMID:The transcriptional activator Imp2p maintains ion homeostasis in Saccharomyces cerevisiae. 961 Dec


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