The hepatitis B virus X-gene product trans-activates both RNA polymerase II and III promoters.

Aufiero, Barbara; Schneider, Robert J.

doi:10.1002/j.1460-2075.1990.tb08136.x

Cited by 153 publications

(94 citation statements)

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“…Our studies represent the first example of a virusmediated event that induces RNA pol III gene activity through TFIIIB. Preliminary studies suggested that the HBV X protein enhances RNA pol III gene activity by targeting TFIIIC (2). In this study, results obtained from template commitment assays suggested that the DNA-binding activity of TFIIIC might be altered in Chang liver (CL) cells stably transformed with the X gene.…”

Section: Figmentioning

confidence: 78%

“…These studies provide further evidence that X mediates an increase in TFIIIB activity which is responsible for the enhanced transcriptional capacity of the X-S2 cell extracts that was observed. Although these results demonstrate that X mediates a change in the TFIIIB component, previous studies suggested that X may target TFIIIC and alter its DNA-binding activity (2). Therefore, the relative activities of TFIIIC derived from the S-2 and X-S2 cell extracts were determined (Fig.…”

Section: Stably Transformed S-2 Cells Expressing Hbv X Exhibit Enhancmentioning

confidence: 85%

“…Previously, the HBV X protein was shown to transactivate the adenovirus VA RNA1 gene promoter (2). We have used the RNA pol III transcription system as a model for understanding the mechanism of X in the transactivation of cellular genes.…”

mentioning

confidence: 99%

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The Hepatitis B Virus X Protein Increases the Cellular Level of TATA-Binding Protein, Which Mediates Transactivation of RNA Polymerase III Genes

Wang

Yuh

Dang

et al. 1995

Molecular and Cellular Biology

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The hepatitis B virus X gene product transactivates a variety of cellular and viral genes. The mechanism for X induction of RNA polymerase (pol) III genes was investigated. By using Drosophila S-2 cells stably transformed with the X gene, the transient expression of a tRNA gene is enhanced. Comparing the transcriptional activities of extracts derived from these cells, all three types of RNA pol III promoters are stimulated by X. Interestingly, both S-2 and rat 1A cells stably transformed with the X gene produce increased cellular levels of the TATA-binding protein (TBP). By using various kinase inhibitors, it was found that the X-mediated increases in both transcription and TBP are dependent upon protein kinase C activation. Since TBP is a subunit of TFIIIB, the activity of this component fractionated from extracts derived from control and X-transformed cells was analyzed. These studies reveal that TFIIIB activity is substantially more limiting in control cells and that TFIIIB isolated from X-transformed cells has increased activity in reconstitution assays compared with TFIIIB isolated from control cells. Conversely, comparison of TFIIIC from control and X-transformed cell extracts revealed that there is relatively little change in its ability either to reconstitute transcription or to bind to DNA and that there is no change in the catalytic activity of RNA pol III. Studies were performed to determine whether directly increasing cellular TBP alone could enhance RNA pol III gene transcription. Transient expression of a TBP cDNA in rat 1A cells was capable of stimulating transcription activity from the resultant extracts in vitro. Together, these results demonstrate that one mechanism by which X mediates transactivation of RNA pol III genes is by increasing limiting TBP via the activation of cellular signaling pathways. The discovery that X increases cellular TBP, the universal transcription factor, provides a novel mechanism for the function of a viral transactivator protein and may explain the ability of X to produce such large and diverse effects on cellular gene expression.The hepatitis B virus (HBV) encodes four genes, one of which produces a 154-amino-acid polypeptide, X, which is known to transactivate a large variety of cellular and viral RNA polymerase (pol) II promoters as well as an RNA pol III promoter (51). There is evidence that X may play a significant role in the development of hepatocellular carcinoma, which occurs with high incidence following chronic infection by HBV (35). Hence, the mechanism of action of X has been the subject of intense study. The mechanism for X transactivation is not yet clear; however, several distinct models have been proposed. X does not bind to DNA directly, but several studies have provided evidence that X may interact with specific DNAbinding proteins to activate transcription. X has been shown to stimulate transcription when targeted to specific DNA-binding sites by fusion of X with heterologous DNA-binding domains (39,45). Other studies have demonstrated direct pro...

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Section: Figmentioning

confidence: 78%

Section: Stably Transformed S-2 Cells Expressing Hbv X Exhibit Enhancmentioning

confidence: 85%

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The Hepatitis B Virus X Protein Increases the Cellular Level of TATA-Binding Protein, Which Mediates Transactivation of RNA Polymerase III Genes

Wang

Yuh

Dang

et al. 1995

Molecular and Cellular Biology

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“…SV40 T antigen is a transactivator of polIII (72), which increases activity of TFIIIC by changing its abundance or phosphorylation state (73). TFIIIC has been shown to be the rate-limiting factor in the formation of polIII initiation complexes (71) and probably the target of trans-activators (74). The ability of X-protein to activate polIII is due to its interaction with TFIIIB rather than TFIIIC (69).…”

Section: Discussionmentioning

confidence: 99%

Rat B2 Sequences Are Induced in the Hippocampal CA1 Region After Transient Global Cerebral Ischemia

Liu¹,

Clemens

Yin

et al. 1999

Journal of Biological Chemistry

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Global brain ischemia causes cell death in the CA1region of the hippocampus 3-5 days after reperfusion. The biological pathway leading to such delayed neuronal damage has not been established. By using differential display analysis, we examined expression levels of poly(A) RNAs isolated from hippocampal extracts prepared from rats exposed to global ischemia and found an up-regulated transcript, clone 17a. Northern blot analysis of clone 17a showed an approximately 35-fold increase in the ischemic brain at 24 h after four-vessel occlusion. Rapid amplification of cDNA ends of clone 17a revealed a family of genes (160 -540 base pairs) that had the characteristics of rodent B 2 sequences. In situ hybridization demonstrated that the elevated expression of this gene was localized predominantly in the CA1 pyramidal neurons. The level of expression in the CA1 region decreased dramatically between 24 and 72 h after ischemia. The elevated expression of clone 17a was not observed in four-vessel occlusion rats treated with the compound LY231617, an antioxidant known to exert neuroprotection in rats subjected to global ischemia. Since delayed neuronal death has the characteristics of apoptosis, we speculate that clone 17a may be involved in apoptosis. We examined the expression level of clone 17a in in vitro models of apoptosis using cerebellar granule neurons that were subjected to potassium removal, glutamate toxicity, or 6-hydroxydopamine treatment and found that clone 17a transcripts were induced in cerebellar granule neurons by glutamate or 6-hydroxydopamine stimulation but not potassium withdrawal.A short period of global cerebral ischemia in rodents causes neurons in the striatum, hippocampus, and lateral thalamus to die (1). Intriguingly, pyramidal neurons in the CA1 region of the hippocampus undergo delayed neuronal death 3-5 days after the insult (1, 2). A similar phenomenon occurs in human cerebral ischemia (3). This time lag provides a window of opportunity for therapeutic interventions after ischemic injury. However, the molecular mechanisms that trigger and lead to delayed neuronal death have not been well established, although many hypotheses have been proposed such as excitotoxicity of glutamate, disturbed calcium homeostasis, altered lipid metabolism, free radicals, and mitochondrial involvement (for reviews, see Refs. 4 and 5). There is a growing body of evidence suggesting that apoptotic events occur in both global and focal brain ischemia (6 -8). It is possible that many of these hypotheses may in fact represent different aspects of a common mechanism. One of the approaches that can be used to further our understanding of the molecular mechanism of delayed neuronal death is to establish the gene expression profile of the process. Differential expression of many genes has been observed in ischemic brains, including some immediate early genes, heat shock proteins, and factors controlling apoptosis such as Bcl2, Bcl-x, Bax, and caspases (for reviews, see Refs. 9 and 10).Differential display (DD) 1 is a techn...

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“…The HBx responsible cis-elements present in RNA polymerase II (RNAPII) promoters include AP-1, AP-2, ATF, c/EBP, NF-B sites, and serumresponsive element (3)(4)(5)(6)(7)(8)(9)(10)(11). One of the RNA polymerase III promoters is also transactivated by HBx (12). Several endogenous genes important for cell proliferation and acute inflammatory response, such as c-fos, c-jun, and human interleukin-8, are activated by HBx (3,7,13).…”

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confidence: 99%

Hepatitis B Virus X Protein Is a Transcriptional Modulator That Communicates with Transcription Factor IIB and the RNA Polymerase II Subunit 5

Lin

Nomura

Cheong

et al. 1997

Journal of Biological Chemistry

158

174

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Hepatitis B virus X protein (HBx) transactivates viral and cellular genes through a wide variety of cis-elements. However, the mechanism is still obscure. Our finding that HBx directly interacts with RNA polymerase II subunit 5 (RPB5), a common subunit of RNA polymerases, implies that HBx directly modulates the function of RNA polymerase (Cheong, J. H., Yi, M., Lin, Y., and Murakami, S. (1995) EMBO J. 14, 142-150). In this context, we examined the possibility that HBx and RPB5 interact with other general transcription factors. HBx and RPB5 specifically bound to transcription factor IIB (TFIIB) in vitro, both of which were detected by either far-Western blotting or the glutathione S-transferaseresin pull-down assay. Delineation of the binding regions of these three proteins revealed that HBx, RPB5, and TFIIB each has two binding regions for the other two proteins. Co-immunoprecipitation using HepG2 cell lysates that express HBx demonstrated trimeric interaction in vivo. Some HBx substitution mutants, which had severely impaired transacting activity, exhibited reduced binding affinity with either TFIIB or RPB5 in a mutually exclusive manner, suggesting that HBx transactivation requires the interactions of both RPB5 and TFIIB. These results indicated that HBx is a novel virus modulator that facilitates transcriptional initiation by stabilizing the association between RNA polymerase and TFIIB through communication with RPB5 and TFIIB.

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The hepatitis B virus X-gene product trans-activates both RNA polymerase II and III promoters.

Abstract: The transcriptional regulatory activity of the human hepatitis B virus (HBV) X-gene product was

Cited by 153 publications

References 50 publications

The Hepatitis B Virus X Protein Increases the Cellular Level of TATA-Binding Protein, Which Mediates Transactivation of RNA Polymerase III Genes

The Hepatitis B Virus X Protein Increases the Cellular Level of TATA-Binding Protein, Which Mediates Transactivation of RNA Polymerase III Genes

Rat B2 Sequences Are Induced in the Hippocampal CA1 Region After Transient Global Cerebral Ischemia

Hepatitis B Virus X Protein Is a Transcriptional Modulator That Communicates with Transcription Factor IIB and the RNA Polymerase II Subunit 5

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