Research focus

Mitotic control of chromosome segregation

During mitosis, faithful chromosome segregation requires that sister chromatids are held together until all chromosomes are properly aligned at the metaphase plate. Prior to the onset of anaphase, sister chromatids are linked to each other by DNA catenation and cohesin protein complex, which encloses sister chromatids by a ring-like structure. Both the resolution of DNA catenation and the dissociation of cohesin from chromatids are controlled by the spindle assembly checkpoint (SAC), which monitors stable microtubule-kinetochore attachments or the presence of tension over sister centromeres upon chromosome biorientation. Thus, the integrity of SAC signaling is essential for genomic integrity following cell division.

Protein shugoshin-1 (Sgo1), named by the guardian spirit in Japanese, is a centromere-localized protein that functions in protecting premature dissociation of cohesins from centromeres. Interestingly, Sgo1 shows dynamic localizations in response to the presence of centromeric tension, suggesting a potential role of Sgo1 on the SAC signaling. We propose that mitotic phosphorylation of Sgo1 by polo-like kinase-1 (Plk1) may regulate the translocation and functionality of Sgo1 and that subsequently contributes to the SAC silencing.

Ongoing projects:

1. Study the underlying mechanism leading to the upregulation of Sgo1 in cancer cells (Lyu-Han Wang)

2. Characterize the expression of different Sgo1 isoforms in various cancer cells and the dominant effect of Sgo1 overexpression (Tian-Neng Lee)

3. Study the role of Sgo1 overexpression on the mitotic progression (Joseph Tio)

Hepatitis B Virus (HBV)-mediated hepatocyte polyploidy and aneuploidy

Hepatitis B virus (HBV) is the major etiologic factor for the development of hepatocellular carcinoma (liver cancer). Viral oncoproteins, such as X protein (HBx) and pre-S mutant large surface proteins (LHBs), are believed to play a role in hepatocarcinogenesis. HBx acts as a very strong gene transactivator that stimulates several intracellular signaling pathways to promote cell proliferation and survival. In addition, naturally occurred mutants carrying deletions over pre-S1 and pre-S2 regions are frequently detected in patients with hepatocellular carcinoma. Notably, liver cancers were developed in transgenic mice with either HBx or pre-S2 mutant LHBs, suggesting positive roles of these two viral products in HBV-mediated hepatocarcinogenesis.

Unlike other organisms, polyploidy is frequently detected in the liver and the present of which often indicates terminal differentiation or cell senescence. Increase in hepatocyte polyploidy may occur to compensate the loss of liver mass or functions under pathological conditions. Notably, polyploid hepatocytes often stay in a quiescent stage with a marked decrease in replication capacity. However, hepatocytes carrying HBV oncoproteins are able to escape cell senescence even in the presence of polyploid genome, suggesting a role of HBV oncoproteins on hepatocyte proliferation. In the present study we propose that the expression of HBV oncoproteins in hepatocytes contribute to both the generation and the following cell cycle control of polyploid hepatocytes. We anticipate that the investigation on the control mechanism of hepatocyte polyploidy may shed light on future treatments for hepatocellular carcinoma and liver regeneration.

Ongoing projects:

1. The role of HBV pre-S mutant proteins in hepatocyte polyploidy and aneuploidy (Kuan-Ying Lu)

3. The role of ER stress on hepatocyte motility and centrosome duplication (Anderson Yang)

4. Explore the role of HBV oncoproteins on the expression of essential mitotic regulators as well as mitotic progression (Yi-Ning Pei)

Epstein-Barr virus, Nasopharyngeal carcinoma, and Hodgkin lymphoma

Ongoing projects:

1. Explore how is EBV reactivation achieved on nasopharyngeal carcinoma cells (Yi-Ru Liu)

2. Explore the underlying mechanism leading to the formation of Reed-Sternberg cells upon EBV infection (Yi-Ru Liu)