The core focus of our lab is on the pathways regulating the entry and progression of mitosis, the activity of which is fundamental and central to the maintenance of genomic stability. The pathways regulating those processes also have direct link to the cellular proliferation with the determination of cell fate in general and specifically in cancer. We aim to develop genomic-scale molecular information from genetic screening, biochemical analysis, cell biological analysis, and mouse models to generate datasets of which evaluation and interpretation will underlie the development of a comprehensive and integrated understanding of the complex oncogenic signaling networks. Since cross-talk and other properties of the networks directly reflect cancer development and treatment response, we will use this data to build further understanding of cancer development and integrate this information into the study of clinical phenotypes and the search of therapeutic targets.

Mammalian Aurora kinases family members, Aurora kinase A, -B and -C, have recently taken centre stage in the regulation of key cell cycle processes. Aurora-A is a critical regulator of centrosome and spindle function. Aurora-B mediates chromosome segregation by ensuring proper biorientation of sister chromatids, through the regulation of microtubule dynamics. Aurora-B also functions in cytokinesis. Importantly, all human aurora kinases are overexpressed in many types of cancers, and the level of expression in a cancer correlates well with chromosomal instability and their grade of malignancy. Overexpression of Aurora A also causes resistance to cell death induced by mitotic damage in human cancer cells by overriding spindle checkpoint which delays cells from entering and exiting mitosis under conditions that can compromise genome integrity. Moreover, Aurora A functionally interacts with other tumor suppressor proteins and oncogenes such as p53, BRCA1 and Ras.

Survivin is a member of the inhibitor of apoptosis (IAP) family and is an essential regulator of cell proliferation, differentiation and death. Recent studies have led to the identification of multi-functional survivin-mediated signaling pathways that act at the interface between cell cycle progression and cell death inhibition. In addition to its cytoprotective function, survivin has an essential role in mitosis. Survivin is a chromosomal passenger protein and is involved in chromosome segregation, central spindle formation, cytokinesis, and spindle checkpoint maintenance through its interactions with other passenger proteins, inner centromere protein (INCENP) and Aurora-B kinase (Aurora-B). Significantly, the level of survivin expression in a cancer correlates well with patient prognosis.

We created conditional survivin knockout mice in which survivin can be inactivated in a tissue specific manner and showed that survivin signaling pathways are involved in T cell development. Survivin is essential for the proliferation and survival of double negative (DN) thymocytes such that the majority of DN cells die in its absence.

Currently, we are focused on tissue specific function of survivin and identification of molecules that can influence or interact with survivin and Aurora kinase pathways in vivo. We have also initiated genetic screening in Drosophila to identify upstream regulators and downstream targets for the Aurora kinases. We will identify and characterize the molecules which functionally interact with those pathways.

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