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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HBx protein of hepatitis B virus (HBV) is a transcriptional activator that is required for infection and may play an important role in HBV-associated hepatocarcinogenesis. Recently, we and others have shown that HBx stimulates the Ras-Raf-MAP kinase cascade, which leads to enhanced cell proliferation and the activation of transcription factors AP-1 and NF-kappa B. Other studies have shown that HBx can activate transcription by interacting directly with nuclear components of the transcription machinery. Therefore we examined the basis for the different reported activities of HBx. Here, we show that HBx is a complex protein, displaying independent activities in different intracellular locations. The intracellular distribution of HBx protein was first investigated using scanning confocal laser immunomicroscopy and by genetic studies. Our work has established that HBx expressed in cultured cells is found authentically in both the cytoplasm and the nucleus. HBx is not strongly associated with any intracellular structures, but some preferential accumulation was observed near the cell surface. Next, HBx variants were constructed containing a functional or mutant nuclear localization sequence. We show that when HBx is engineered to relocate exclusively to the nucleus, it no longer activates the Ras-Raf-MAP kinase cascade, nor does it activate transcription factors AP-1 and NF-kappa B. Surprisingly, nuclear HBx fully retains the ability to stimulate HBV enhancer I, which is activated independently of the Ras and protein kinase C pathways. Therefore HBx protein stimulates signal transduction pathways in the cytoplasm and transactivates transcription elements in the nucleus. Furthermore, SV40 T antigen is shown to induce the nuclear sequestration of HBx protein and to block its activation of NF-kappa B, demonstrating that HBx is regulated by proteins that alter its intracellular distribution. The conflicting functions of HBx protein in viral infection and possibly carcinoma may involve the regulation of its differential distribution in the cell.
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PMID:The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors. 758 4

The c-fos serum response element (SRE) is necessary and sufficient for induction of the c-fos gene in response to serum and growth factors. This activation is dependent upon serum response factor (SRF), a transcriptional activator which binds the SRE. A factor, p62TCF, which binds in conjunction with SRF to the SRE and which is activated by mitogen-activated protein kinase, has also been implicated in c-fos regulation. By using a reporter gene system with weak SRE mutations that is dependent upon overexpression of SRF for serum induction, we have found that there are at least two pathways for serum induction that converge on the SRE. Loss of TCF binding by mutations in SRF and the SRE did not reduce serum induction of the reporter genes. We have found a pathway for serum induction that is sensitive to mutations in the A/T-containing central sequence of the SRE and which is independent of TCF. When this pathway was mutated, activation was dependent upon TCF binding, demonstrating that TCF can also function in serum induction. Both of the signalling pathways required a minimal domain of SRF. This domain, spanning SRF's DNA binding domain, was sufficient for serum induction when fused to a heterologous transcriptional activation domain.
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PMID:Two pathways for serum regulation of the c-fos serum response element require specific sequence elements and a minimal domain of serum response factor. 806 25

CHOP, a member of the C/EBP family of transcription factors, mediates effects of cellular stress on growth and differentiation. It accumulates under conditions of stress and undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, CHOP is phosphorylated on these residues by p38 mitogen-activated protein kinase (MAP kinase). A specific inhibitor of p38 MAP kinase, SB203580, abolished the stress-inducible in vivo phosphorylation of CHOP. Phosphorylation of CHOP on these residues enhanced its ability to function as a transcriptional activator and was also required for the full inhibitory effect of CHOP on adipose cell differentiation. CHOP thus serves as a link between a specific stress-activated protein kinase, p38, and cellular growth and differentiation.
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PMID:Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. 865 May 47

The coordinated cellular responses to physiological stress are known to be effected in part by the activation of heat-shock factor 1, a transcriptional activator protein capable of binding to, and inducing transcription from genes containing heat shock elements. Other stress responsive signal transduction pathways also exist including the stress activated protein kinase cascade that regulates the activity of the transcription factor AP1. We have examined the expression of the low molecular stress proteins, heat shock protein 27 and alpha B-crystallin in astrocytes in response to physiological stress of different types and asked what component of this induction is effected at the transcriptional level and whether activation of heat shock factor 1 and AP1 might account for these events. We have found that stress regulated induction of alpha B-crystallin has a strong transcriptional component and that it may be effected by at least two different transcriptional mechanisms. In one set of phenomena, represented here by cadmium exposure, alpha B-crystallin and heat shock protein 27 are coordinately regulated and this occurs in the presence of activated heat shock factor 1. In the second series of phenomena, represented here by hypertonic stress, alpha B-crystallin is induced in the absence of heat shock factor activation and in the absence of any corresponding change in heat shock protein 27 expression. Although hypertonic stress does activate an AP1-like binding activity, the AP1 consensus binding site in the alpha B-crystallin promoter does not appear to be a target for this hypertonic stress inducible activity. These data suggest that the hypertonic stress response is effected through a heat shock factor independent mechanism and that hypertonic stress regulated induction of alpha B-crystallin does not directly depend on the SAPK pathway and AP1 activity.
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PMID:Transcription regulation of alpha B-crystallin in astrocytes: analysis of HSF and AP1 activation by different types of physiological stress. 874 50

The hepatitis B virus (HBV) genome encodes a 154 amino acid protein termed X (HBx, hepatitis B x protein), which is a promiscuous transcriptional activator of polymerase II and III promoters. HBx upregulates a wide range of cellular and viral genes and is thought to facilitate viral pregenome and mRNA transcription; however, its precise role in the viral replication cycle remains to be elucidated. The functional mechanisms of HBx appear very complex. It was shown to activate transcription factors AP-1 and NF-kappa B vis cytoplasmic pathways including ras-MAP kinase. In contrast, nuclear HBx is thought to activate the transcriptional machinery directly. A second transcriptional activator protein (Mst, middle s transactivator) is encoded by 3'-truncated preS2/S sequences of integrated HBV DNA, but not by the intact viral gene. HBx and Mst may contribute to the pathogenicity of chronic hepatitis B and are suggested to promote hepatocyte transformation via upregulation of cellular proto-oncogenes. Further, HBx may enhance HBV related carcinogenesis by inactivation of the tumour suppressor gene product p53.
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PMID:Hepatitis B virus transcriptional activators: mechanisms and possible role in oncogenesis. 887 69

Chicken embryo fibroblasts (CEF) transformed with v-src were previously reported to revert to normal phenotype after the introduction of dominant-negative mutants of Fos or Jun, indicating that endogenous AP-1 activity is essential for the cellular transformation. The major changes in the expression levels of fos and jun family genes induced by v-src were the elevation of fra-2 and c-jun transcripts. We show here that extensive phosphorylation of the AP-1 component Fra-2 is a major qualitative change in v-src transformed CEF and that several Ser and Thr residues in a C-terminal region of Fra-2 (amino acids 266-323) are phosphorylated specifically. The induced kinase activity was detected at the position of 42 kDa by in gel kinase assay using the Fra-2 C-terminal region as a substrate, and it was identified as chicken ERK2. JNK1 and JNK2, other members of the MAP kinase family, were not significantly activated in v-src transformed CEF and Fra-2 was not a good substrate for JNKs. fra-2 promoter analysis indicated that this promoter activity is elevated in v-src transformed CEF via two AP-1 binding sites and CRE-like sequence. We propose that phosphorylation of Fra-2 by ERK2 converts it from an inefficient transcriptional activator to an active one and further that fra-2 expression is autoregulated in response to the phosphorylation status of its gene product.
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PMID:Phosphorylation and high level expression of Fra-2 in v-src transformed cells: a pathway of activation of endogenous AP-1. 918 58

NF-kappa B is a ubiquitous transcription factor that contributes to the induction of many genes playing a central role in immune and inflammatory responses. The NF-kappa B proteins are subject to multiple regulatory influences including post-translational modifications such as phosphorylation and proteolytic processing. A very important component of this regulation is the control of their subcellular localization: cytoplasmic retention of NF-kappa B is achieved through interaction with I kappa B molecules. In response to extracellular signals, these molecules undergo degradation, NF-kappa B translocates to the nucleus and activates its target genes. To investigate novel proteins involved in this dynamic response, we have reconstituted the NF-kappa B/I kappa Beta system in the yeast Saccharomyces cerevisiae. We have successively introduced p65, the main transcriptional activator of the NF-kappa B family, which leads to the activation of two reporter genes controlled by kappa B sites, and the I kappa B alpha inhibitory protein, which abolishes this activation. By transforming such a yeast strain with a cDNA library we have performed a genetic screen for cDNAs encoding proteins capable of either dissociating the p65/I kappa B alpha complex or directly transactivating the expression of the reporter genes. The efficiency of our screen was demonstrated by the isolation of a cDNA encoding the p105 precursor of the p50 subunit of NF-kappa B. We also used this system to test stimuli known to activate signalling pathways in yeast, in order to investigate whether the related mammalian cascades might be involved in NF-kappa B activation. We showed that yeast endogenous kinase cascades activated by pheromone, hypo- or hyperosmotic shock cannot modulate NF-kappa B activity in our system, and that the p38 human MAP kinase does not act directly on the p65/I kappa B alpha complex.
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PMID:Reconstitution of the NF-kappa B system in Saccharomyces cerevisiae for isolation of effectors by phenotype modulation. 920 Aug 10

In the yeast Saccharomyces cerevisiae, Ste12p induces transcription of pheromone-responsive genes by binding to a DNA sequence designated the pheromone response element. We generated a series of hybrid proteins of Ste12p with the DNA-binding and activation domains of the transcriptional activator Gal4p to define a pheromone induction domain of Ste12p sufficient to mediate pheromone-induced transcription by these hybrid proteins. A minimal pheromone induction domain, delineated as residues 301 to 335 of Ste12p, is dependent on the pheromone mitogen-activated protein (MAP) kinase pathway for induction activity. Mutation of the three serine and threonine residues within the minimal pheromone induction domain did not affect transcriptional induction, indicating that the activity of this domain is not directly regulated by MAP kinase phosphorylation. By contrast, mutation of the two tyrosines or their preceding acidic residues led to a high level of transcriptional activity in the absence of pheromone and consequently to the loss of pheromone induction. This constitutively high activity was not affected by mutations in the MAP kinase cascade, suggesting that the function of the pheromone induction domain is normally repressed in the absence of pheromone. By two-hybrid analysis, this minimal domain interacts with two negative regulators, Dig1p and Dig2p (also designated Rst1p and Rst2p), and the interaction is abolished by mutation of the tyrosines. The pheromone induction domain itself has weak and inducible transcriptional activity, and its ability to potentiate transcription depends on the activity of an adjacent activation domain. These results suggest that the pheromone induction domain of Ste12p mediates transcriptional induction via a two-step process: the relief of repression and synergistic transcriptional activation with another activation domain.
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PMID:Transcriptional activation upon pheromone stimulation mediated by a small domain of Saccharomyces cerevisiae Ste12p. 934 3

The let-23 receptor/mpk-1 MAP kinase signaling pathway induces the vulva in C. elegans. We show that MPK-1 directly regulates both the LIN-31 winged-helix and the LIN-1 Ets transcription factors to specify the vulval cell fate. lin-31 and lin-1 act genetically downstream of mpk-1, and both proteins can be directly phosphorylated by MAP kinase. LIN-31 binds to LIN-1, and the LIN-1/LIN-31 complex inhibits vulval induction. Phosphorylation of LIN-31 by MPK-1 disrupts the LIN-1/LIN-31 complex, relieving vulval inhibition. Phosphorylated LIN-31 may also act as a transcriptional activator, promoting vulval cell fates. LIN-31 is a vulval-specific effector of MPK-1, while LIN-1 acts as a general effector. The partnership of tissue-specific and general effectors may confer specificity onto commonly used signaling pathways, creating distinct tissue-specific outcomes.
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PMID:MAP kinase signaling specificity mediated by the LIN-1 Ets/LIN-31 WH transcription factor complex during C. elegans vulval induction. 960 32

Ets transcription factors are important downstream targets of oncogenic Ras. The transcriptional activity of several Ets family members is regulated by Ras, and interfering with Ets-dependent transcription by expression of just the Ets2 DNA binding domain can inhibit or reverse Ras-mediated cellular transformation. To better understand the role of Ets proteins in Ras transformation, we have now analyzed the effects of stably expressing a variety of Ets2 constructs in Ras-transformed NIH3T3 (DT) cells. Expression of only the Ets2 transactivation domains, which also inhibits Ras or Neu/ErbB-2-mediated activation of Ets-dependent transcription, strongly inhibited anchorage-independent growth, but did not revert the transformed DT cell morphology. Unexpectedly, high expression of full-length Ets2, a transcriptional activator, broadly reversed the transformed properties of DT cells, including anchorage-independent growth, transformed morphology, and tumorigenicity, but did not impair attached cell growth. Increasing full-length Ets2 transcriptional activity by fusing it to the VP16 transactivation domain enhanced its ability to reverse DT cell transformation. Mutational analysis revealed that the mitogen-activated protein kinase phosphorylation site required for Ras-mediated activation, Ets2(T72), was not essential for Ets2 reversion activity. The distinct reversion activities of the highly expressed Ets2 transactivation domains or full-length Ets2, along with the specific reversion activity by Ets2 constructs that either inhibit or activate Ets-dependent transcription, suggests multiple roles for Ets factors in cellular transformation. These results indicate that several distinct approaches for modulating Ets activity may be useful for intervention in human cancers.
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PMID:Elevated expression of Ets2 or distinct portions of Ets2 can reverse Ras-mediated cellular transformation. 966 63


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