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 mechanism by which human immunodeficiency virus type 1 Tat transactivates the long terminal repeat promoter is not understood. It is generally believed that Tat has one or more transcription factors as its cellular target. One might expect a cellular target for Tat to possess several properties, including (i) the ability to bind to the Tat activation region, (ii) the possession of a transcriptional activation domain, and (iii) the ability to contact the cellular transcription machinery. Here we describe the cloning, expression, and characterization of a human protein, termed TAP (Tat-associated protein), which possesses some of these properties. TAP is highly conserved in eukaryotes and is expressed in a variety of human tissues. The major intracellular species of TAP is a highly acidic 209-amino-acid protein that likely is formed by removal of a highly basic 70-amino-acid N-terminal segment from a primary translation product. By deletion analysis, we have identified a TAP C-terminal region rich in acidic amino acids and leucine residues which acts as a strong transcriptional activator when bound through GAL4 sites upstream of the core long terminal repeat promoter, as well as flanking sequences that mask the activation function. Amino acid substitution of two leucine residues within the core activation region results in loss of the TAP activation function. Two lines of evidence suggest that Tat interacts with TAP in vivo. First, promoter-bound Tat can recruit a TAP/VP16 fusion protein to the promoter. Second, transiently expressed Tat is found associated with endogenous TAP, as demonstrated by coimmuno-precipitation analysis. As shown in an accompanying report, the TAP activation region binds the Tat core activation region and general transcription factor TFIIB (L. Yu, P.M. Loewenstein, Z. Zhang, and M. Green, J. Virol. 69:3017-3023, 1995). These combined results suggest the hypothesis that TAP may function as a coactivator that bridges Tat to the general transcription machinery of the cell via TFIIB.
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PMID:Molecular cloning and characterization of a cellular protein that interacts with the human immunodeficiency virus type 1 Tat transactivator and encodes a strong transcriptional activation domain. 770 27

In Schizosaccharomyces pombe, the iron sensor Fep1 mediates the transcriptional repression of iron transport genes in response to high concentrations of iron. On the other hand, fep1(+) expression is downregulated under conditions of iron starvation by the CCAAT-binding factor Php4. In this study, we created a fep1Delta php4Delta double mutant strain where expression of fep1(+) was disengaged from its iron limitation-dependent repression by Php4 to examine the effects of iron on constitutively expressed functional fep1(+)-GFP and TAP-fep1(+) alleles and their gene products. In these cells, Fep1-green fluorescent protein was invariably localized in the nucleus under both iron-limiting and iron-replete conditions. Using chromatin immunoprecipitation assays, we found that Fep1 is associated with iron-responsive promoters in vivo. Chromatin binding was iron dependent, with a loss of binding observed in the presence of low iron. Functional dissection of the protein revealed that the N-terminal 241-residue segment that includes two consensus Cys(2)/Cys(2)-type zinc finger motifs and a Cys-rich region is required for optimal promoter occupancy by Fep1. Within this segment, a minimal module encompassing amino acids 60 to 241 is sufficient for iron-dependent chromatin binding. Using yeast one-hybrid analysis, we showed that the replacement of the repression domain of Fep1 by fusing the activation domain of VP16 to the chromatin-binding fragment of amino acids 1 to 241 of Fep1 converts the protein from an iron-dependent repressor into an iron-dependent transcriptional activator. Thus, the repression function of Fep1 can be replaced with that of a transcriptional activation function without the loss of its iron-dependent DNA-binding activity.
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PMID:Iron activates in vivo DNA binding of Schizosaccharomyces pombe transcription factor Fep1 through its amino-terminal region. 1925 22

To arise and progress, cancers need to evade immune elimination. Consequently, progressing tumors are often MHC class I (MHC-I) low and express immune inhibitory molecules, such as PD-L1, which allows them to avoid the main antitumor host defense, CD8+ T cells. The molecular mechanisms that led to these alterations were incompletely understood. In this study, we identify loss of the transcription factor IRF2 as a frequent underlying mechanism that leads to a tumor immune evasion phenotype in both humans and mice. We identified IRF2 in a CRISPR-based forward genetic screen for genes that controlled MHC-I Ag presentation in HeLa cells. We then found that many primary human cancers, including lung, colon, breast, prostate, and others, frequently downregulated IRF2. Although IRF2 is generally known as a transcriptional repressor, we found that it was a transcriptional activator of many key components of the MHC-I pathway, including immunoproteasomes, TAP, and ERAP1, whose transcriptional control was previously poorly understood. Upon loss of IRF2, cytosol-to-endoplasmic reticulum peptide transport and N-terminal peptide trimming become rate limiting for Ag presentation. In addition, we found that IRF2 is a repressor of PD-L1. Thus, by downregulating a single nonessential gene, tumors become harder to see (reduced Ag presentation), more inhibitory (increased checkpoint inhibitor), and less susceptible to being killed by CD8+ T cells. Importantly, we found that the loss of Ag presentation caused by IRF2 downregulation could be reversed by IFN-stimulated induction of the transcription factor IRF1. The implication of these findings for tumor progression and immunotherapy are discussed.
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PMID:Frequent Loss of IRF2 in Cancers Leads to Immune Evasion through Decreased MHC Class I Antigen Presentation and Increased PD-L1 Expression. 3147 24