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

Wang, Horng-Dar; Yuh, Chiou-Hwa; Dang, Chi V.; Johnson, Deborah L.

doi:10.1128/mcb.15.12.6720

Cited by 66 publications

(78 citation statements)

References 54 publications

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“…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). During X-protein activation, polIII catalytic activity remains unchanged.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…Adenovirus E1A (63), simian virus 40 T antigens (64), X-protein of the human hepatitis B virus (65), and Tax protein of the human T-cell leukemia virus type 1 (66) are known to trigger apoptosis in mammalian cells. On the other hand, cells transformed with these agents exhibit an increased level of polIII transcripts (67)(68)(69)(70).…”

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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“…In addition, the accumulation of RNA pol III transcripts around the nucleolus is particularly evident in transformed cells (17). Many types of virus-trans-formed cell lines display enhanced production of RNA pol III transcripts, including those transformed with simian virus 40 (18), papovavirus (19), and viral products such as hepatitis B virus X protein (20) and human T-cell leukemia virus type 1 Tax protein (21). Overproduction of RNA pol III transcripts has been observed in a wide variety of human tumors.…”

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confidence: 99%

Enhanced RNA Polymerase III-dependent Transcription Is Required for Oncogenic Transformation*

Johnson

Dubeau

Johnson

2008

Journal of Biological Chemistry

108

121

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RNA polymerase (pol) III transcription, responsible for the synthesis of various stable RNAs, including 5 S rRNAs and tRNAs, is regulated by oncogenic proteins and tumor suppressors. Although it is well established that RNA pol III-dependent transcription is deregulated in transformed cells and malignant tumors, it has not been determined whether this represents a cause or consequence of these processes. We show that Rat1a fibroblasts undergoing oncogenic transformation by the TATAbinding protein or c-Myc display enhanced RNA pol III transcription. Decreased expression of the RNA pol III-specific transcription factor Brf1 prevented this increase in RNA pol III transcription. Although the overall proliferation rates of these cells remained unchanged, the ability of cells to grow in an anchorage-independent manner and form tumors in mice was markedly reduced. Although overexpression of Brf1 modestly stimulated RNA pol III transcription, expression of a phosphomimic, Brf1-T145D, more significantly induced transcription. However, these increases in transcription were not sufficient to promote cellular transformation. Together, these results demonstrate that enhanced RNA pol III transcription is essential for anchorage-independent growth and tumorigenesis and that these events can be uncoupled from effects on anchorage-dependent proliferation. RNA polymerase (pol)2 III synthesizes a variety of small untranslated RNAs, including tRNA, 5 S rRNA, U6 RNA, and 7SL RNA. RNA pol III products play essential roles in protein synthesis, RNA processing, and protein trafficking. rRNA synthesis by RNA pol I and pol III is a limiting step in ribosome accumulation (1), and the overall rate of translation is determined by the number of ribosomes (2). Thus, the rate of RNA pol I and pol III transcription dictates the biosynthetic capacity of cells and may be an important determinant of a cell's capacity to grow. Consistent with this idea, decreasing RNA pol I transcription has been shown to result in reduced cellular growth rates (3). Recent results showed that decreased RNA pol III transcription by the bacterial compound Tagetin prevented hypertropic enlargement of cardiomyocytes (4). Activation of RNA pol III-dependent transcription may thus be needed for increased cell mass.RNA pol III transcription is regulated by a variety of tumor suppressors and oncogenes. Oncogenic Ras (5), c-Myc (6), and activated phosphatidylinositol 3-kinase (7) all serve to induce transcription, whereas the tumor suppressors Rb (8), p53 (9), and PTEN (7) repress RNA pol III transcription. The RNA pol III-specific transcription factor (TF) IIIB complex, composed of TATA-binding protein (TBP), Brf1, and Bdp1, is the target of these regulatory proteins. Both Rb and p53 interact directly with components of the TFIIIB complex to inhibit its function, whereas c-Myc stimulates RNA pol III transcription by directly associating with the TFIIIB complex and enhancing its recruitment to promoters. In contrast, through its ability to regulate phosphatidylinositol 3-ki...

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“…Consistent with this notion, increases in cellular TBP have been shown to have pronounced effects on cellular transcription. We have demonstrated that all three classes of RNA polymerase III-dependent promoters are stimulated in response to increased levels of TBP, either directly (34) or indirectly by the expression of the HBV X protein (41) or the activation of protein kinase C by phorbol ester (13,14). Evidence supports the idea that this is a result of increased numbers of functional TBP-containing TFIIIB complexes at these promoters (34,41).…”

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confidence: 99%

“…Our previous studies have demonstrated that expression of the hepatitis B virus (HBV) X protein in both mammalian and insect cells produces an increase in the cellular levels of TBP (41). Since the X protein has been shown to be a promiscuous transcriptional transactivator, its ability to increase TBP likely contributes to its effect on a large and diverse number of viral and cellular promoters.…”

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confidence: 99%

Transcriptional Regulation of the TATA-Binding Protein by Ras Cellular Signaling

Johnson

Mandavia

Wang

et al. 2000

Molecular and Cellular Biology

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Our previous studies have demonstrated that the level of the central transcription factor TATA-binding protein (TBP) is increased in cells expressing the hepatitis B virus (HBV) X protein through the activation of the Ras signaling pathway, which serves to enhance both RNA polymerase I and III promoter activities. To understand the mechanism by which TBP is regulated, we have investigated whether enhanced expression is modulated at the transcriptional level. Nuclear run-on assays revealed that the HBV X protein increases the number of active transcription complexes on the TBP gene. In transient-transfection assays with both transformed and primary hepatocytes, the human TBP promoter was shown to be induced by expression of the HBV X protein in a Ras-dependent manner, requiring both Ral guanine nucleotide dissociation stimulator (Ral-GDS) and Raf signaling. Transient overexpression of TBP did not affect TBP promoter activity. To further delineate the downstream Ras-mediated events contributing to TBP promoter regulation in primary rat hepatocytes, the best-characterized Ras effectors, Raf, phosphoinositide 3-kinase (PI-3 kinase), and RalGDS, were examined. Activation of either Raf or RalGDS, but not that of PI-3 kinase, was sufficient to induce TBP promoter activity. Both Raf-and RalGDS-mediated induction required the activation of mitogen-activated protein kinase kinase (MEK). In addition, another distinct Ras-activated pathway, which does not require MEK activation, appears to induce TBP promoter activity. Analysis of the DNA sequence requirement within the TBP promoter responsible for these regulatory events defined three distinct regions that modulate the abilities of Raf, RalGDS, and the Ras-dependent, MEK-independent pathways to regulate human TBP promoter activity. Together, these results provide new evidence that TBP can be regulated at the transcriptional level and identify three distinct Ras-activated pathways that modulate this central eukaryotic transcription factor.The TATA-binding protein (TBP) is a central factor used in the transcription of all eukaryotic genes (18). TBP is assembled into at least three distinct protein complexes, SL1, transcription factor IID (TFIID), and TFIIIB, by its association with different TBP-associated factors, which then specifies its role in the transcription of the RNA polymerase I, II, and III promoters, respectively. In promoters containing a TATA element, these TBP complexes are recruited through direct interaction of TBP with the DNA. In contrast, TBP is recruited to promoters that lack a TATA element via protein-protein interactions. The recruitment of TBP to TATA-containing promoters has been shown to be a rate-limiting step for transcription activation (for a review, see reference 27). Thus, alterations in the cellular levels of TBP could produce global changes in cellular gene activity.Although the role of TBP in the formation of transcription initiation complexes has been well studied, little is known regarding potential cellular events that might regulate th...

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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

Cited by 66 publications

References 54 publications

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

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

Enhanced RNA Polymerase III-dependent Transcription Is Required for Oncogenic Transformation*

Transcriptional Regulation of the TATA-Binding Protein by Ras Cellular Signaling

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