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 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

The Pax-5 gene codes for the transcription factor BSAP which is essential for the progression of adult B lymphopoiesis beyond an early progenitor (pre-BI) cell stage. Although several genes have been proposed to be regulated by BSAP, CD19 is to date the only target gene which has been genetically confirmed to depend on this transcription factor for its expression. We have now taken advantage of cultured pre-BI cells of wild-type and Pax-5 mutant bone marrow to screen a large panel of B lymphoid genes for additional BSAP target genes. Four differentially expressed genes were shown to be under the direct control of BSAP, as their expression was rapidly regulated in Pax-5-deficient pre-BI cells by a hormone-inducible BSAP-estrogen receptor fusion protein. The genes coding for the B-cell receptor component Ig-alpha (mb-1) and the transcription factors N-myc and LEF-1 are positively regulated by BSAP, while the gene coding for the cell surface protein PD-1 is efficiently repressed. Distinct regulatory mechanisms of BSAP were revealed by reconstituting Pax-5-deficient pre-BI cells with full-length BSAP or a truncated form containing only the paired domain. IL-7 signalling was able to efficiently induce the N-myc gene only in the presence of full-length BSAP, while complete restoration of CD19 synthesis was critically dependent on the BSAP protein concentration. In contrast, the expression of the mb-1 and LEF-1 genes was already reconstituted by the paired domain polypeptide lacking any transactivation function, suggesting that the DNA-binding domain of BSAP is sufficient to recruit other transcription factors to the regulatory regions of these two genes. In conclusion, these loss- and gain-of-function experiments demonstrate that BSAP regulates four newly identified target genes as a transcriptional activator, repressor or docking protein depending on the specific regulatory sequence context.
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PMID:Identification of BSAP (Pax-5) target genes in early B-cell development by loss- and gain-of-function experiments. 954 44

Pax5 (BSAP) functions as both a transcriptional activator and repressor during midbrain patterning, B-cell development and lymphomagenesis. Here we demonstrate that Pax5 exerts its repression function by recruiting members of the Groucho corepressor family. In a yeast two-hybrid screen, the groucho-related gene product Grg4 was identified as a Pax5 partner protein. Both proteins interact cooperatively via two separate domains: the N-terminal Q and central SP regions of Grg4, and the octapeptide motif and C-terminal transactivation domain of Pax5. The phosphorylation state of Grg4 is altered in vivo upon Pax5 binding. Moreover, Grg4 efficiently represses the transcriptional activity of Pax5 in an octapeptide-dependent manner. Similar protein interactions resulting in transcriptional repression were also observed between distantly related members of both the Pax2/5/8 and Groucho protein families. In agreement with this evolutionary conservation, the octapeptide motif of Pax proteins functions as a Groucho-dependent repression domain in Drosophila embryos. These data indicate that Pax proteins can be converted from transcriptional activators to repressors through interaction with corepressors of the Groucho protein family.
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PMID:Transcriptional repression by Pax5 (BSAP) through interaction with corepressors of the Groucho family. 1081 20

Pax5 (BSAP) is essential for B cell development and acts both as a transcriptional activator and a repressor. Using a yeast two-hybrid assay to identify potential coregulators of Pax5, we identified Daxx, a protein that is highly conserved, ubiquitously expressed, and essential for embryonic mouse development. The interaction between Pax5 and Daxx involves the partial homeodomain of Pax5 and the C-terminal fragment of Daxx. A component of promyelocytic leukemia protein nuclear bodies, Daxx has been implicated in apoptosis and characterized as a transcriptional corepressor. Upon transient transfection assay of Daxx in B cells expressing endogenous Daxx and Pax5, we observed not only transcriptional corepression but also, unexpectedly, coactivation in M12.4.1 and A20 mouse B cell lines. Pax5 domains required for coactivation were identified using 293T cells. Coactivation apparently involves recruitment of the CREB binding protein (CBP), because we precipitated complexes containing Pax5, Daxx, and CBP in B cell lines. These data suggest that Daxx can affect Pax5's roles as an activator or repressor in B cells and describe a role for Daxx as a transcriptional coactivator.
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PMID:The interaction of Pax5 (BSAP) with Daxx can result in transcriptional activation in B cells. 1179 27

A role for histone acetylation, which can alter the accessibility of DNA to transcriptional regulatory proteins and contribute to gene expression, in regulating terminal B cell differentiation was investigated in the mature B lymphoma L10A and mouse splenic B cells. Incubation of the L10A cells with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and butyrate increased expression of Blimp-1, J chain, and mad genes, decreased expression of c-myc and BSAP/Pax-5 genes, increased the expression of surface CD43 and Syndecan-1, and decreased surface IgM. Incubation of splenic B cells with TSA and dextran conjugated anti-IgD Ab increased Blimp-1 gene and Syndecan-1 surface expression. The alteration in gene expression and cell surface markers was consistent with induction of the onset of terminal B cell differentiation. Co-incubation of L10A cells with TSA and cycloheximide (CHX) abrogated the up-regulation of Blimp-1 expression, indicating that TSA-activated Blimp-1 expression required synthesis of a transcriptional activator. In contrast, mad expression was increased in L10A cells cultured with TSA and cycloheximide or cycloheximide alone, suggesting mad expression may occur independent of Blimp-1 expression and is regulated by a labile, HDAC associated transcriptional repressor. The results demonstrate that histone acetylation regulates transcription of genes controlling terminal B cell differentiation.
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PMID:Activation of terminal B cell differentiation by inhibition of histone deacetylation. 1269 18

Prostate cancer (PCa) is one of the major malignancies affecting males' health around the world. Long noncoding RNAs (lncRNAs), a class of long transcripts, has been reported as essential regulators in tumorigenesis. IDH1 antisense RNA 1 (IDH1-AS1) is an lncRNA which can interact with genes to regulate the Warburg effect. However, function and mechanism of it in tumorigenesis of PCa remains unclear. Therefore, our current study focused on exploring the role of IDH1-AS1 in PCa tumor growth. At first, the expression of IDH1-AS1 was identified to be upregulated in PCa samples and cell lines. Mechanism associated with the upregulation of IDH1-AS1 was analyzed and demonstrated by mechanism experiments. The result suggested that PAX5 is the transcriptional activator of IDH1-AS1. Functionally, loss-of function assays revealed that silencing of IDH1-AS1 inhibited cell proliferation and induced cell apoptosis both in vitro and in vivo. Through microarray analysis and Gene ontology (GO) analysis, we determined that IDH1-AS1 can affect PCa cell autophagy by upregulating ATG5 expression. Mechanism investigation further validated that IDH1-AS1 posttranscriptionally regulated ATG5 expression by enhancing the mRNA stability of ATG5 or upregulating ATG5 by sequestering miR-216b-5p. Consequently, rescue assays demonstrated that IDH1-AS1 promoted proliferation and apoptosis in PCa via ATG5-induced autophagy. Taken together, our study elucidated the function and regulatory mechanism of IDH1-AS1, thus providing a novel biomarker for PCa.
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PMID:PAX5-induced upregulation of IDH1-AS1 promotes tumor growth in prostate cancer by regulating ATG5-mediated autophagy. 3157 Jul 3