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 expression of the 7B2 protein, secreted from a variety of neural and endocrine tissues, increases dramatically in specific neuroendocrine tumors. We have recently shown that human 7B2 can act as a molecular chaperone in the deaggregation of proteins in vitro. In order to identify polypeptides which might bind 7B2 in vivo, the yeast two-hybrid system was employed. Surprisingly, mere covalent linkage of 7B2 to the DNA-binding domains of two yeast transcription activators, Ace1 and Gal4, activates transcription from the ACE1 and GAL4 operon. 7B2's ability to activate nuclear transcription surpasses that of Ace1 and compares favourably with the strong activation domain of the tumor suppressor protein, p53. Our results suggest that 7B2 must possess an activating sequence, a domain which defines all transcriptional activator proteins. Like the acidic activation domains of some transcriptional activators, 7B2 also binds the yeast TATA-box binding protein, an essential polypeptide in the basic transcription machinery. Deletion analysis of the gene encoding 7B2 reveals two independent transcriptional activating sequences in the 185 amino acid protein. It is therefore conceivable that 7B2 not only has a functional role in the secretory pathway but also in the nucleus. Moreover, these findings raise an intriguing question regarding the activation domains of 7B2 and their possible link to 7B2's oncogenic potential.
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PMID:The neuroendocrine protein 7B2 contains unusually potent transcriptional activating sequences. 748 73

The conformation of the C-terminal DNA-binding domain of the transcriptional activator NifA from Klebsiella pneumoniae has been probed by circular dichroism (CD), Fourier-transformed infrared (FT-IR), and nuclear magnetic resonance (NMR) spectroscopy in combination. Secondary structure prediction suggests that the C-terminal half of the domain contains three alpha-helices. The spectra show that the domain is folded in the absence of DNA and of the N-terminal and central domains of NifA. The three spectroscopic techniques suggest slightly different proportions of secondary structural elements but all suggest that it contains about 33% alpha-helix. These results are in agreement with a previous prediction suggesting that NifA contains a helix-turn-helix motif and with the amount of alpha-helix predicted. The environment of the aromatic residues was examined by CD and NMR spectroscopy, which suggest that one or both of the tryptophan residues are involved in the tertiary structure of the protein but that the tyrosine residue in the helix-turn-helix motif is solvent exposed and so available to bind to DNA. The thermal melting profiles and pH-dependent structural changes were also examined by CD spectroscopy. This technique indicates that at low pH there is an increase in the secondary structure and interactions contributing to the tertiary structure. Many of the acidic residues are predicted to be on a single helix, before the helix-turn-helix motif, which may therefore be important for maintaining the structure and function of the C-terminal peptide; alternatively, the N-terminal half of the domain may become more folded at low pH.
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PMID:Secondary structure of the C-terminal DNA-binding domain of the transcriptional activator NifA from Klebsiella pneumoniae: spectroscopic analyses. 988 44

The function of the alphaherpesvirus UL47 tegument protein has not yet been defined. Nonetheless, previous studies with transfected cells have shown that both the herpes simplex virus type 1 homologue (hUL47, or VP13/14) and the bovine herpesvirus type 1 (BHV-1) homologue (bUL47, or VP8) have the capacity to shuttle between the nucleus and the cytoplasm. Furthermore, hUL47 packaged into the virion has also been shown to bind several individual virus-specific RNA transcripts. Here, we extend these observations and show that hUL47 binds a wide range of RNA species in vitro. It has a high affinity for polyadenylated transcripts but has no apparent selectivity for virus-encoded RNA over cellular RNA. We also show that the virion population of bUL47 binds RNA in vitro. However, while purified recombinant hUL47 retains its RNA binding activity, recombinant bUL47 does not, suggesting that the BHV-1 homologue may require virus-induced modification for its activity. We identify the minimal RNA binding domain in hUL47 as a 26-residue N-terminal peptide containing an arginine-rich motif that is essential but not sufficient for optimal RNA binding, and we demonstrate that this RNA binding domain incorporates the hUL47 minimal nuclear localization signal. In addition, we show that soon after hUL47 is expressed during infection, it colocalizes in the infected cell nucleus with ICP4, the major virus transcriptional activator. Using RNA immunoprecipitations, we demonstrate that hUL47 is also bound in vivo to at least one viral transcript, the ICP0 mRNA. Taken together, these results suggest that hUL47 may play a role in RNA biogenesis in the infected cell.
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PMID:RNA binding by the herpes simplex virus type 1 nucleocytoplasmic shuttling protein UL47 is mediated by an N-terminal arginine-rich domain that also functions as its nuclear localization signal. 1716 2

MrpC, a member of the CRP/Fnr superfamily of transcriptional regulators, plays a key role in coordination of the multicellular developmental program in Myxococcus xanthus. Previous reports suggest MrpC is subject to complex regulation including activation by an unusual LonD-dependent proteolytic processing event that removes its unique N-terminal peptide, producing the isoform MrpC2. MrpC2 is proposed to positively autoregulate and regulate transcription of hundreds of genes necessary for both the aggregation and sporulation phases of the developmental program. We demonstrate here that mrpC expression bifurcates corresponding to different cell populations within the developmental program. During our analysis of regulatory events controlling this process, we demonstrate that MrpC2 is not an active isoform; rather, the N-terminal peptide is instead essential for MrpC function in vivo. We also demonstrate that MrpC is instead a negative autoregulator and represses its own expression by specifically competing with its enhancer binding protein, MrpB. These results provide an additional rare example of CRP / EBP coordinated regulation, and significantly revise the model for control of the central developmental transcriptional activator of the M. xanthus developmental program. This article is protected by copyright. All rights reserved.
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PMID:MrpC, a CRP/Fnr homolog, functions as a negative autoregulator during the Myxococcus xanthus multicellular developmental program. 2974 42

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