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Dysregulation of cell surface proteolysis has been strongly implicated in tumorigenicity and metastasis. In this study, we delineated the role of hepatocyte growth factor activator inhibitor-2 (HAI-2) in prostate cancer (PCa) cell migration, invasion, tumorigenicity and metastasis using a human PCa progression model (103E, N1, and N2 cells) and xenograft models. N1 and N2 cells were established through serial intraprostatic propagation of 103E human PCa cells and isolation of the metastatic cells from nearby lymph nodes. The invasion capability of these cells was revealed to gradually increase throughout the serial isolations (103E

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To explore more hNinein interacting proteins, the yeast two-hybrid screening using ninein C-terminal domain as bait protein was performed. One novel gene, CGI-99, was demonstrated to associate with hNinein in the yeast two-hybrid method and in vitro GST pull-down assay. Molecular characterization also showed that CGI-99 possessed a transcriptional activity at the N-terminal. In addition, CGI-99 formed a dimer with the C-terminal, which overlapped with hNinein binding site. In kinase assay, CGI-99 binds to hNinein and completely blocks the phosphorylation of hNinein by GSK3beta. Moreover, CGI-99 was highly expressed in all brain tumors which is in agreement with the Northern blot analysis. Taken together, we have isolated a novel protein CGI-99, which may be involved in the functional regulation of human ninein in the centrosome structure and may also be important in brain development and tumorigenesis.

Hepatitis delta antigen (HDAg) is a nuclear protein that is intimately involved in hepatitis delta virus (HDV) RNA replication. HDAg consists of two protein species, the small form (S-HDAg) and the large form (L-HDAg).Previous studies have shown that posttranslational modifications of S-HDAg, such as phosphorylation, acetylation, and methylation, can modulate HDV RNA replication. In this study, we show that S-HDAg is a small ubiquitin-like modifier 1 (SUMO1) target protein. Mapping data showed that multiple lysine residues are SUMO1 acceptors within S-HDAg. Using a genetic fusion strategy, we found that conjugation of SUMO1 to S-HDAg selectively enhanced HDV genomic RNA and mRNA synthesis but not antigenomic RNA synthesis. This result supports our previous proposition that the cellular machinery involved in the synthesis of HDV antigenomic RNA is different from that for genomic RNA synthesis and mRNA transcription, requiring different modified forms of S-HDAg. Sumoylation represents a new type of modification for HDAg.Hepatitis delta virus (HDV) causes chronic and, occasionally, fulminant hepatitis in humans (16). HDV is a satellite virus which requires hepatitis B virus (HBV) to supply envelope proteins for virus assembly and production (46). It contains a circular RNA genome of 1.7 kb which replicates through a double-rolling-circle mechanism in the nucleus (33). The viral genomic RNA (G-RNA) is first replicated into the full-length antigenomic RNA (AG-RNA) and is also transcribed into a 0.8-kb mRNA, which encodes the only HDV protein, hepatitis delta antigen (HDAg). The AG-RNA, in turn, is replicated into G-RNA by another round of rollingcircle replication. The production of HDAg, which is intimately involved in HDV RNA replication, is a unique feature distinguishing HDV from plant viroids, which do not encode any protein. HDAg consists of two species, the small delta antigen (S-HDAg) (195 amino acids [aa]; 24 kDa) and the large delta antigen (L-HDAg) (214 aa; 27 kDa), which play different roles in HDV replication. S-HDAg is an essential activator for HDV RNA replication (25). In contrast, L-HDAg inhibits certain stages of HDV RNA replication but is required for virion assembly (5,7,28,32). HDAg has been shown to be modified posttranslationally by phosphorylation (6, 9, 40, 42), acetylation (41), methylation (29), and in the case of L-HDAg, isoprenylation (14). Arg-13 methylation, Lys-72 acetylation, and Ser-177 phosphorylation are three major modifications of S-HDAg and are important for the functions of S-HDAg in HDV RNA replication (29,40,41,48). Isoprenylation on Cys-211 of L-HDAg is required for virus assembly (14). SUMO (small ubiquitin-related modifier) has been identified as a reversible posttranslational protein modifier (34, 35). The human genome encodes four SUMO proteins: SUMO1 to SUMO4 (13,17). Among them, SUMO1 to SUMO3 are ubiquitously expressed, whereas SUMO4 is expressed mainly in the kidneys, lymph nodes, and spleen (17). Sumoylation is carried out by an E1 activating enzyme (the heterodimer...