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Centrosome Amplification and Cancer


School of Biomedical Sciences

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Dr Y Ching Applications accepted all year round Funded PhD Project (Students Worldwide)

About the Project

Centrosome, which is the microtubule-organising center (MTOC) in the cell, plays a critical role in determining the motility, polarity and division of cell. Strong evidence suggests that supernumerary centrosomes drive chromosomal instability and is linked to oncogenesis. While aneuploidy is frequently observed in human cancer cells, targeting the cancer cells with dysregulated centrosome function may represent a novel approach of cancer therapy. Several viral oncoproteins, such as human papillomavirus (HPV) type 16 E6 and E7 and hepatitis B virus X protein (HBx), have also been shown to transform cells by promoting centrosome abnormalities and formation of multipolar spindles. These data appear that induction of centrosome amplification may be a common strategy for viral-mediated oncogenesis.

There are four major groups of centrosome kinase, including Polo-like kinase (PLK), Aurora kinase, Cyclin-dependent protein kinase (CDK) and NIMA-related kinase (NEK), that are believe to play important role in regulating centrosome activity, cell cycle progression and cell polarity. Interestingly, inhibitors of these kinases have actively been explored for inhibiting cancer cell growth. Recently, we have characterized a novel centrosome protein, we named TAX1BP2, which plays a critical role in blocking centrosome over-duplication. TAX1BP2 is also targeted by human T cell leukemia virus (HTLV-I) to create chromosome instability and aneuploidy. TAX1BP2 is located at the centrosomal linker region, which is important for the cohesion of centrioles. We showed that TAX1BP2 is a putative tumor suppressor in liver cancer (hepatocellular carcinoma, HCC) and is regulated by CDK2 kinase. Our recent study has also shown that TAX1BP2 is a novel substrate of DNA damage response kinase, ATM. We also observed that several centrosome kinases, including PLK4 and NEK2, were deregulated in HCC and may regulate TAX1BP2 by phosphorylation. In this project, we would like to understand further the molecular signaling of TAX1BP2 and how centrosome overduplication contributes to the development of cancer.
Supervisor
After obtaining his B.Sc. in Biochemistry at Imperial College, University of London UK, Dr. Ching continued his PhD training in Department of Biochemistry at University of Dundee, Scotland UK. He returned to Hong Kong and had his post-doctoral training in Hong Kong University of Science and Technology and Institute of Molecular Biology at The University of Hong Kong. He has been appointed as Research Assistant Professor in the Department of Pathology and Assistant Professor in the Department of Anatomy at the same university since 2007. Currently, he is a tenured Associate Professor in The University of Hong Kong. Dr. Ching has long-standing interest in studying the molecular signaling in the development hepatocellular carcinoma.

Faculty information, funding opportunities and application deadlines: https://www.findaphd.com/phds/program/biomedical-research-hku-li-ka-shing-faculty-of-medicine/?i586p4119

References

Xu HT, Lai WL, Liu HF, Wong LL, Ng IO, Ching YP. “PAK4 Phosphorylates p53 at Serine 215 to Promote Liver Cancer Metastasis.” Cancer Research (2016) Oct 1;76(19):5732-5742.

Lai WL, Hung WH, *Ching YP. “The tumor suppressor, TAX1BP2, is a novel substrate of ATM kinase.” Oncogene (2014) Nov 6; 33(45): 5303-9
Lai WL, Hung WY, Wong LL, Zhou Y, Leong VY, Lee JMF, Ng IOL, Jin DY, *Ching YP. The centrosomal protein Tax1 binding protein 2 is a novel tumour suppressor in hepatocellular carcinoma regulated by cyclin-dependent kinase 2. Hepatology (2012) 56(5): 1770-1781

Mak GW, Chan ML, Leong VY, Lee JM, Yau TO, Ng IOL, *Ching YP. Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis. Cancer Research (2011) 71(8): 2949-2958

*Ching YP, Leong VYL, Lee MF, Xu HT, Jin DY, *Ng IOL. Pak1 is overexpressed in hepatocellular carcinoma and enhances cancer metastasis involving JNK activation and paxillin phosphorylation. Cancer Research (2007) 67:3601-3608

Ching YP, Chan SF, Jeang KT, Jin DY. Retroviral oncoprotein Tax targets coiled-coil centrosomal protein TAX1BP2 to induce centrosome overduplication. Nature Cell Biology (2006) 8: 717-724
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