Hepatitis B virus X protein regulates transactivation activity and protein stability of the cancer-amplified transcription coactivator ASC-2

Abstract

H epatitis B virus (HBV) mainly infects liver tissue and is associated with hepatitis and hepatocellular carcinoma. 1 Several findings suggest that HBV X protein (HBx) could be a causative factor in progression of these diseases. 2 HBx protein is known to regulate transcription of a variety of cellular and viral genes, although it does not bind to double-stranded DNA. The observation that genes stimulated by HBx lack any obvious consensus sequences suggests that HBx stimulates transcription by interacting with cellular proteins and/or components of signal transduction pathways. Consistent with this hypothesis, HBx has been shown to directly interact with transcriptional factors such as RPB5 of RNA polymerase, 3 TATA-binding protein, 4 and bZIP proteins 5 and leads to activation of signal transduction pathways including the Ras/Raf/mitogen-activated protein kinase, protein kinase C, Jak1-STAT, and nuclear factor B pathways. [6][7][8][9] Activating signal cointegrator 2 (ASC-2) is a recently identified transcriptional coactivator of nuclear receptors. 10 Similar, if not identical, molecules have been identified by others and variously termed TRBP, PRIP, and RAP250. 11-14 ASC-2, a typical ligand and AF2-dependent interactor of nuclear receptors, enhances receptor transactivation, either alone or in conjunction with SRC-1 and CBP/p300. Interestingly, ASC-2 is identical to AIB3, which was identified as a transcript that was overexpressed in human breast cancers. 15 ASC-2 can mediate transactivation of mitogenic transcription factors including SRF, AP-1, and nuclear factor B. 16 This observation suggests that overexpression of ASC-2 may promote tumorigenesis, consistent with the observation that ASC-2 copy number was amplified and overexpressed in cancer cell lines including BT-474, ZR-75-1, and MCF7.Interestingly, both HBx and ASC-2 proteins are capable of interacting with AP-1 and retinoid X receptor (RXR) transcription factors and function in a cooperative manner in specific transcriptional regulation. 16,17 These

HBx Protein Contributes to Liver Carcinogenesis by H3K4me3 Modification Through Stabilizing WD Repeat Domain 5 Protein

“…It's interesting to note that HBx can exert its function on the ubiquitin protein degradation system in either a positive or negative manner . Many studies have demonstrated that HBx can interact with and hijack ubiquitin ligase to target proteins for degradation; yet, other studies have found that HBx can also inhibit ubiquitin ligase and thus stabilize target proteins, such as Pituitary Tumor‐Transforming Gene 1, protein arginine N‐methyltransferase 1, and Amplified in Breast Cancer 1, as we found for WDR5 in this study. Although the HBx‐E3 ubiquitin ligase interaction may inhibit ubiquitination of target proteins, thereby stabilizing them, the underlying mechanism still needs to be elucidated.…”

Modulation of Androgen Receptor Transactivation by the SWI3-Related Gene Product (SRG3) in Multiple Ways

“…For example, Jab1 (Jun activation domain-binding protein 1) interacts with HIF-1␣ (hypoxia-inducible factor 1␣) and enhances HIF-1␣ stability, resulting in an increase in the HIF-1␣ protein level (1). In a similar way, hepatitis B virus X protein and p300 increase the half-life of activating signal cointegrator 2 and sterol regulatory element binding proteins (SREBPs), respectively (19,31). Thus, the increase of protein stability by protein-protein interaction is likely another action mode of transcription factor/coactivator to enhance gene expression.…”

“…SRG3 upregulates the SRC-1 protein level. Interactions between two coactivators or between a nuclear receptor and its coactivator have been reported to increase the stability of one of the participant proteins, resulting in an upregulation of the protein level (1,19,31). Because SRG3 cooperated with SRC-1 in the enhancement of AR transactivation, most likely via physical association, we examined the effect of SRG3 on the SRC-1 protein level in HeLa cells cotransfected with AR, SRC-1, and the control ␤-galactosidase expression plasmids with or without the SRG3 expression vector.…”

Hepatitis B Virus X Protein Impairs Hepatic Insulin Signaling Through Degradation of IRS1 and Induction of SOCS3

“…m67-Luc construct (high-affinity binding site for Stats followed by the luciferase gene) was kindly provided from Dr. Jacqueline Bromberg [30]. pcDNA3/HA/HBx derived from HBV adr subtype, pGL3B/PEPCK promoter, and pCMX1/C/EBPα were previously described [6], [31], [32].…”