Hepatitis B computer virus X (HBX) is essential for the productive contamination of hepatitis B computer virus (HBV) in vivo and has a pleiotropic effect on host cells. the proteasome were reduced in the HBX transgenic mouse liver, whereas the activity of another cellular protease was elevated, suggesting a compensatory mechanism in protein degradation. In the microarray analysis, diverse genes were altered in the HBX mouse livers and the number of genes with significant changes increased progressively with age. Functional clustering showed that a quantity of genes involved in transcription and cell growth were significantly affected in the HBX mice, possibly accounting for the observed pleiotropic effect of HBX. In particular, insulin-like growth factor-binding protein 1 was down-regulated in the HBX mouse liver. The down-regulation was similarly observed during acute woodchuck hepatitis computer virus contamination. Other changes including up-regulation of proteolysis-related genes may also contribute to the profound alterations of liver functions in HBV contamination. Hepatitis B computer virus (HBV) is a member of the hepadnaviridae family that includes the hepatitis viruses of the woodchuck, ground squirrel, tree squirrel, Peking duck, and heron. HBV has a fourth open reading frame, termed the hepatitis B computer virus X (HBX) gene. The HBX gene is usually well conserved among the mammalian hepadnaviruses and codes for any 16.5-kDa protein. The protein can activate the transcription of a variety of viral and cellular genes (3, 9). Since HBX does not bind to DNA directly, its activity is usually thought to be mediated via protein-protein interactions. HBX has been shown to enhance transcription through AP-1 and AP-2 (5, 27) and to activate numerous transmission transduction pathways (10, 11). Several studies have also recognized possible cellular targets of HBX, including members of the CREB/ATF family (23), the TATA-binding protein (25), RNA polymerase subunit RPB5 (8), the UV-damaged DNA-binding protein (28), and Cilengitide the mitochondrial protein (32). HBX has also been shown to interact with p53 and inhibit its function (30, 31). Furthermore, X protein is necessary for the establishment of productive contamination in vivo (7, 39). Recent results also exhibited that signaling through calcium may mediate a function of HBX in viral replication (6). We have previously demonstrated that this proteasome complex is a cellular target of HBX (16, 17) and that this interaction is usually functionally important in the pleiotropic effect Cilengitide of HBX (37, 38). Two subunits of the 26S proteasome complex, PSMA7 and PSMC1, were identified as putative targets of HBX by using a yeast two-hybrid system. This interaction is usually specific using an in vitro binding assay, comigration in sucrose gradient, and coimmunoprecipitation (16, 37). Functional assay showed that HBX could lead to the inhibition of peptidase and proteinase activities of the proteasome complex in tissue culture (16). The transactivating activity of HBX was specifically inhibited by proteasome-specific inhibitors, such as MG132 and lactacystin, in a dose-dependent manner, whereas calpain protease inhibitor ALLM has no effect. Because proteasome plays a crucial role in diverse cellular functions ranging from cell differentiation, cell cycle control, transmission transduction, stress response, transcriptional activation, DNA repair, apoptosis, and antigen presentation, the conversation between HBX and the proteasome complex may represent an important pathway for the biological functions of HBX. In the woodchuck model, we exhibited that X-deficient Rabbit Polyclonal to DP-1 mutants of woodchuck hepatitis computer virus (WHV) are not completely defective, behaving like attenuated viruses (38). Our experiments also suggested that this function of HBX in HBV replication may be medicated through a proteasome-dependent pathway (36). In cells infected with either the recombinant adenovirus-HBV or baculovirus-WHV, the replication of the wild-type Cilengitide computer virus was not affected, while the replication of X-minus computer virus of either HBV or WHV was enhanced and restored to Cilengitide Cilengitide the wild-type level by proteasome inhibitors. To further understand the role of HBX in the viral life cycle and the pathogenesis of HBV, we analyzed the effects of HBX on proteasome activities in vivo and the global gene expression profiles by microarray analysis in a transgenic mouse model expressing the HBX gene. In this model, the HBX expression is developmentally regulated by the mouse major urinary protein (MUP) promoter in the liver (15). We here demonstrate that this proteasome activities were inhibited in the HBX mice and an unrelated cellular protease complex, the Tricon protease, was activated at the same time, suggesting.