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 AmpR transcriptional activator for the chromosomal ampC beta-lactamase gene of Citrobacter freundii was found to interact with an operator sequence located in the 5' half of the 38 bp region protected by AmpR in DNase I footprinting experiments. AmpR binding was associated with significant DNA bending of target DNA. A glycine to glutamic acid alteration at position 102 in AmpR converts AmpR into a transcriptional activator even in the absence of beta-lactam inducer. AmpRG102E interacted with the operator binding sequence and induced DNA bending. A glycine to lysine alteration at residue 102 completely abolished the ability of AmpR to transcriptionally affect the ampC promoter, i.e. to repress in the absence of beta-lactam inducer and induce in the presence of beta-lactam. Nevertheless, AmpRG102K could repress the oppositely orientated ampR promoter. AmpRG102K could also specifically interact with the operator but the resulting complex migrated faster in gel retardation experiments and no significant DNA bending was observed.
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PMID:Interactions of wild-type and mutant AmpR of Citrobacter freundii with target DNA. 796 33

This review describes a range of pH responses. Some are only induced if relevant DNA is brought to an appropriately supercoiled configuration by DNA gyrase and bent by the action of, for example, integration host factor (IHF). Bending may allow transcription by bringing activators into juxtaposition with RNA polymerase, which is CysB-associated in several of the responses. Control of arginine decarboxylase (AdiA) synthesis at acid pH is of the above type, with dependence on the presence of gyrase, H-NS, IHF and CysB; acid induction of LysU has similar requirements but also needs Lrp; lysine decarboxylase (CadA) formation at acid pH is controlled quite differently, needing the CadC activator and interaction of lysine/lysine permease; H-NS probably reverses induction by CadC. The Hyd components of formic hydrogenlyase are induced by acid under anaerobiosis; a transcriptional activator is involved and Fur may also function in regulation. Acid tolerance induced at low pH in log-phase cells needs CysB and PhoE but not DNA gyrase; tolerance is reduced by NaCl but not affected by Fe3+, Fe2+, glucose/cAMP or by lrp, him, fur, hns or nhaA/B lesions. Alkali tolerance (habituation), induced at pH0 8.5-9.0, probably involves DNA supercoiling and bending; the induction process needs IHF, CysB, PhoE, NhaA, TonB and Fur and is glucose-repressed; tolerance may result from Na+ efflux catalysed by the NhaA antiporter, which is induced at pH0 9.0. Alkali sensitivity induced at pH0 5.5 also requires gyrase, IHF and CysB, but H-NS, Lrp, NhaA and OmpC are also needed and induction is abolished by NaCl. Salt-induced acid sensitivity results from PhoE formation and is blocked by glucose (reversed by cAMP), FeCl3 and hns and relA lesions, the effect of relA being envZ-suppressed. Acid sensitivity induction (ASI) at pH0 9.0 needs H-NS, is inhibited by FeCl3 and amiloride, and is associated with alkyl hydroperoxide reductase synthesis. Leucine-induced acid sensitivity needs gyrase, CysB, H-NS, Fur, OmpA and RelA, is inhibited by Fe3+, Fe2+, tetracycline, glucose and nalidixic acid, but not by chloramphenicol; increased outer membrane proton passage may result from OmpA modification.
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PMID:Regulatory components, including integration host factor, CysB and H-NS, that influence pH responses in Escherichia coli. 917 36

The HIV Tat protein, primarily characterized as a transcriptional activator of the viral long terminal repeat (LTR), is also a potent repressor of major histocompatibility complex (MHC) class I transcription. In the present study, we demonstrate that these two functional activities are distinct and mediated by discrete, but overlapping, structural domains of Tat. Tat repressor activity depends on C-terminal sequences, whereas transactivation depends on N-terminal sequences; both functions require core sequences. The repressor activity requires a domain encompassing the region encoded by the second exon of the Tat gene, beginning at amino acid 73, with a C-terminal limit between amino acids 80 and 83. Tat repressor function also depends on the presence of a lysine at position 41, located within the core of the protein. Tat repressor activity is independent of two N-terminal domains essential for transactivation: the acidic segment and the cysteine-rich region. Conversely, Tat transactivation is independent of the second exon-encoded region of Tat. As further support for this novel model of separable Tat functions, we show that in murine fibroblasts, Tat represses class I promoter activity, but does not transactivate the HIV LTR. We propose that distinct structural domains mediate the two functionally distinct activities associated with the Tat protein.
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PMID:HIV Tat protein requirements for transactivation and repression of transcription are separable. 943 53

The expression of the structural genes for lysine (LYS) biosynthesis is controlled by a pathway-specific regulation mediated by the transcriptional activator Lys14 in the presence of alpha-aminoadipate semialdehyde, an intermediate of the pathway acting as a co-inducer. Owing to end product inhibition of the first step of the pathway, excess lysine reduces the production of the co-inducer and causes apparent repression of the LYS genes. Analysis of LYS promoters and insertions within an heterologous reporter gene have allowed the characterization of an upstream activating element (UASLYS) able to confer Lys14- and alpha-amino-adipate semialdehyde-dependent activation as well as apparent repression by lysine to another yeast gene. This DNA motif is present as one of several copies in the promoters of at least six LYS genes. The consensus sequence derived from the comparison of the UASLYS showing the highest activation capacities comprises the nonameric core sequence TCCRNYGGA. The RNY sequence of the 3 bp spacer as well as the presence of flanking AT-rich regions on both sides of the core sequence appear essential for optimal activation. Further evidence that this element is the target of Lys14p was provided by the demonstration that Lys14p binds to UASLYS in vitro. The binding is independent of the presence of the co-inducer and is not affected by lysine. It depends on the integrity of the putative Zn(II)2Cys6 binuclear cluster contained in the Lys14p.
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PMID:A nonameric core sequence is required upstream of the LYS genes of Saccharomyces cerevisiae for Lys14p-mediated activation and apparent repression by lysine. 970 10

Expression of the structural genes for lysine biosynthesis responds to an induction mechanism mediated by the transcriptional activator Lys14p in the presence of alpha-aminoadipate semialdehyde (alphaAASA), an intermediate of the pathway acting as a coinducer. This activation is reduced by the presence of lysine in the growth medium, leading to apparent repression. In this report we demonstrate that Saccharomyces cerevisiae possesses two genes, LYS20 and LYS21, encoding two homocitrate synthase isoenzymes which are located in the nucleus. Each isoform is inhibited by lysine with a different sensitivity. Lysine-overproducing mutants were isolated as resistant to aminoethylcysteine, a toxic lysine analog. Mutations, LYS20fbr and LYS21fbr, are allelic to LYS20 and LYS21, and lead to desensitization of homocitrate synthase activity towards lysine and to a loss of apparent repression by this amino acid. There is a fair correlation between the I0.5 of homocitrate synthase for lysine, the intracellular lysine pool and the levels of Lys enzymes, confirming the importance of the activity control of the first step of the pathway for the expression of LYS genes. The data are consistent with the conclusion that inhibition by lysine of Lys14p activation results from the control of alphaAASA production through the feedback inhibition of homocitrate synthase activity.
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PMID:In Saccharomyces cerevisae, feedback inhibition of homocitrate synthase isoenzymes by lysine modulates the activation of LYS gene expression by Lys14p. 1010 47

The c-myb proto-oncogene product (c-Myb) is a sequence-specific DNA-binding protein that functions as a transcriptional activator. The transcriptional coactivator CREB-binding protein (CBP) binds via its KIX domain to the activation domain of c-Myb and mediates c-Myb-dependent transcriptional activation. CBP possesses intrinsic histone acetyltransferase activity, and can acetylate not only histones but also certain transcriptional factors such as GATA1 and p53. Here we demonstrate that the C/H2 domain of CBP, which is critical for the acetyltransferase activity, also directly interacts with the negative regulatory domain (NRD) of c-Myb. Consistent with this observation, CBP acetylated c-Myb in vitro at Lys(438) and Lys(441) within the NRD. In addition, CBP acetylated c-Myb in vivo not only at the sites found in this study but also at the p300-induced acetylation sites reported recently. Replacement of lysine by arginine at all of these sites dramatically decreased the trans-activating capacity of c-Myb. The results of transcriptional activation assays with c-Myb acetylation site mutants suggested that acetylation of c-Myb at each of these five sites synergistically enhances c-Myb activity. Mutations of these acetylation sites reduced the strength of the interaction between c-Myb and CBP. Thus, acetylation of c-Myb by CBP increases the trans-activating capacity of c-Myb by enhancing its association with CBP. These results demonstrate a novel molecular mechanism of regulation of c-Myb activity.
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PMID:Increased affinity of c-Myb for CREB-binding protein (CBP) after CBP-induced acetylation. 1107 48

Transcription of lysine genes in Saccharomyces cerevisiae is dependent on Lys14p and on alpha-aminoadipate semialdehyde (alphaAASA), an intermediate of the pathway. The two-thirds C-terminal end of Lys14p is sufficient to ensure the activation function of the protein and its modulation by alphaAASA. Here, we show that no single discrete domain of Lys14p is able to activate transcription and that most of the deleted LexA-Lys14p proteins are inactive even in the presence of a high alphaAASA concentration. The point mutations abolishing the activation capacity of Lys14p are distributed all over the entire C-terminal segment. Although the deletion of 20 residues rich in leucine and located downstream of the DNA-binding domain converts Lys14p to a constitutive transcriptional activator, our analysis provides evidence that the modulation process of Lys14p activity does not involve an effector-dependent masking/unmasking mechanism. Furthermore, we show that the protein chaperone Hsp82p is required for full activation of LYS genes by the alphaAASA-activated Lys14p as well as by the constitutive Lys14p. Our results suggest that the proper folding of the two-thirds C-terminal portion of Lys14p is essential not only to activate transcription but also to modulate it according to alphaAASA concentration.
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PMID:The proper folding of a long C-terminal segment of the yeast Lys14p regulator is required for activation of LYS genes in response to the metabolic effector. 1195 10

CooA is the CO-sensing transcriptional activator from Rhodospirillum rubrum, in which CO binding to its heme prosthetic group triggers a conformational change of CooA that allows the protein to bind its cognate target DNA sequence. By a powerful in vivo screening method following the simultaneous randomization of the codons for two C-helix residues, 113 and 116, near the distal heme pocket of CooA, we have isolated a series of novel CooA variants. In vivo, these show very high CO-independent activities (comparable with that of wild-type CooA in the presence of CO) and diminished CO-dependent activities. Sequence analysis showed that this group of variants commonly contains lysine at position 116 with a variety of residues at position 113. DNA-binding analysis of a representative purified variant, L116K CooA, revealed that this protein is competent to bind target DNA with K(d) values of 56 nm for Fe(III), 36 nm for Fe(II), and 121 nm for Fe(II)-CO CooA forms. Electron paramagnetic resonance and electronic absorption spectroscopies, combined with additional mutagenic studies, showed that L116K CooA has a new ligand replacing Pro(2) in both Fe(III) and Fe(II) states. The most plausible replacement ligand is the substituted lysine at position 116, so that the ligands of Fe(III) L116K CooA are Cys(75) and Lys(116) and those in the Fe(II) form are His(77) and Lys(116). A possible explanation for CO-independent activity in L116K CooA is that ligation of Lys(116) results in a repositioning of the C-helices at the CooA dimer interface. This result is consistent with that repositioning being an important aspect of the activation of wild-type CooA by CO.
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PMID:Analysis of the L116K variant of CooA, the heme-containing CO sensor, suggests the presence of an unusual heme ligand resulting in novel activity. 1212 86

The cGvpE protein of Halobacterium salinarum PHH4 has been identified as transcriptional activator for the promoter of the c-gvpA gene encoding the major gas vesicle structural protein cGvpA. Molecular modelling of the carboxy-terminal region of cGvpE suggests that this protein resembles a basic leucine-zipper protein, and mutations in the putative DNA binding domain DNAB completely abolish the activator function in Haloferax volcanii transformants. Mutations in the key residues of the putative leucine-zipper region AH6 of cGvpE confirmed that the three residues V159, L166 and L173 were essential for the activator function of cGvpE at the c-gvpA promoter, whereas the cysteine residue C180 could be altered to a leucine or an aspartate residue without the loss of this function. Mutations in basic residues of helix AH4 demonstrated the importance of the lysine K104 for the activator function of cGvpE. A cGvpE protein containing a his-tag at the C-terminus was still able to activate the expression of c-gvpA in vivo. The cGvpE his-purified from Hf. volcanii formed a dimer in Blue-native polyacrylamide gels that could be resolved into monomers by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Dimers of cGvpE were already seen using SDS-PAGE, but not with cGvpE mutant proteins containing the alterations L166E or L173E/C180L in the leucine zipper. These results imply that the hydrophobic surface of helix AH6 is indeed required for the establishment of cGvpE dimers.
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PMID:A bZIP protein from halophilic archaea: structural features and dimer formation of cGvpE from Halobacterium salinarum. 1212 60

WT1 encodes a zinc finger transcription factor implicated in normal development and tumorigenesis. Germline mutation or deletion of WT1 results in a spectrum of abnormal kidney development, male-to-female intersex disorders, and predisposition to pediatric nephroblastoma, Wilms tumor. Initially thought to encode a transcriptional repressor, WT1-dependent functions are now more clearly linked to its property as a transcriptional activator of genes involved in renal development and sex determination. WT1 is expressed in 4 isoforms as a result of 2 alternative messenger RNA splicing events, the more significant of which encodes the 3 amino acids lysine, threonine, and serine (KTS) between zinc fingers 3 and 4. Although WT1 isoforms lacking KTS act as sequence-specific DNA binding factors, a large body of evidence now implicates the KTS-containing isoforms in RNA processing. In keeping with distinct biochemical mechanisms for these isoforms, genetic data from humans and mice point to separate but partially overlapping roles for WT1 (+KTS) and (-KTS) during genitourinary development. Recently, a hematopoietic model system has been used to study functional properties of WT1 in vitro. WT1 expression in primary hematopoietic cells leads to stage-specific effects that may be relevant to WT1-mediated tumor suppression.
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PMID:Regulation of gene expression by WT1 in development and tumorigenesis. 1221 8


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