Hepatitis B virus transactivator protein X interacts with the TATA-binding protein.

Abstract

Several viral transcriptional activators have been shown to interact with the basal transcription factor TATA-binding protein (TBP). These associations have been implicated in facilitating the assembly of the transcriptional preinitiation complex. We report here that the hepatitis B virus protein X (pX) specifically binds to TBP in vitro. While truncations of the highly conserved carboxyl terminus of TBP abolished this binding, amino-terminal deletions had no effect. Deletion Infection by human hepatitis B virus (HBV) represents a major health problem. It is estimated that over 250 million people are chronically infected worldwide. Chronic infection has been associated with hepatocellular carcinoma (1). The HBV genome encodes four genes whose transcriptional activity is controlled by at least four promoters and two enhancer elements designated I and II. The 16.5-kDa protein X (pX), encoded by the X gene, can activate gene expression from diverse viral and cellular transcriptional control elements (2-7). pX does not interact directly with cis-acting DNA elements. The biochemical mechanism responsible for pX activity in the viral life cycle remains obscure. While little is known regarding the potential interactions between pX and cellular proteins, it is clear from numerous studies that pX may function by a number of distinct mechanisms (7). We have previously shown that pX mediates transcriptional transactivation by engaging in protein-protein interactions (8). pX was shown to enhance the DNA-binding specificity of the transcription factors ATF-2 and CREB. This interaction within the HBV enhancer element I leads to transactivation through the cAMP response element (8). Several cellular genes, including interleukin 8, intercellular adhesion molecule 1, c-myc, and major histocompatibility complex class I and class II genes, have been shown to be activated by pX via distinct transcription factors (9-13). Consistent with these findings, an NF-KB sequence located in the human immunodeficiency virus long terminal repeat was shown to be the target sequence of pX transactivation (5, 6). However, there is no direct evidence for a direct interaction between pX and these factors. pX has also been shown to increase an endogenous protein kinase C activity via signal transduction pathways (14,15). A recent report demonstrated interactions of pX with the p53 tumorsuppressor gene, and it was proposed that this interaction may impede DNA repair of host genes (16). The mechanism(s) by which pX is able to activate gene expression through a variety of promoters/enhancers has been the subject of intense investigation. Of interest is the observation that the general transcriptional factor TFIID [or the TATA-binding protein (TBP)] is the target of transactivation by a large number of viral and cellular factors. These include adenovirus ElA (17), herpes simplex virus 1 VP16 (18), Epstein-Barr virus Zta (19), human cytomegalovirus IE2 (20), human T-cell lymphotropic virus 1 Tax (21), and human immunodeficiency virus Tat (22). I...

p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro

“…The 16.5 kDa HBx protein is a multifunctional transactivator which up-regulates a variety of viral and cellular genes through protein ± protein interactions. In the nucleus, HBx may function as a co-activator by interacting with elements of the transcription machinery (Cheong et al, 1995;Haviv et al, 1998;Qadri et al, 1995), and from cytoplasmic locations by activating Ras/Raf signaling and NF-kB (Benn and Schneider, 1994;Cross et al, 1993;Natoli et al, 1994;Su and Schneider, 1996).…”

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

“…The reported HBx-binding proteins include transcription factors such as TBP (17), RPB5 (18), CREB/ATF2 (19), and Oct-1 (20), a probable DNA repair enzyme (21), a human homologue of Drosophila 20 S proteasome subunit (22,23), and the tumor suppressor p53 (24,25). These findings are so diverse that the mechanism of HBx transactivation remains obscure.…”

The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice

“…Noticeably, trans-acting activity of HBx was rather weak (510-fold activation) in most experimental systems used, and it has not been demonstrated so far in the context of the whole viral genome. HBx does not directly bind DNA and may stimulate gene expression by interacting with transcriptional factors or with elements of the basal transcription machinery (Cheong et al, 1995;Haviv et al, 1995;Maguire et al, 1991;Qadri et al, 1995;Unger et al, 1990;Williams et al, 1995). Other studies support an indirect e ect of HBx by activating signalling pathways mediated by the Ras-Raf-MAPK cascade or by protein kinase C, a function consistent with the predominant cytoplasmic location of HBx in vivo and in most experimental systems (Benn et al, 1994;Kekule et al, 1993;Natoli et al, 1994).…”