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  • Understanding cancer is demanded not only for public health but also for comprehension of basic principles of life. Through decades of research, people have realized that cancer is not caused by breakdown of a single gene. Cancer is, rather, caused by deregulation of multiple genes or pathways. Therefore thorough dissection of each individual pathway governing cell proliferation, differentiation, apoptosis, growth etc, and integration of them will ultimately lead us to understanding cancer and biology. Of the many possible regulatory pathways which are related to cancer progression, our laboratory is mainly focusing on identifying regulatory mechanisms of cell cycle and Hippo pathway.

    The number of cells in an animal is determined by the regulation of cell proliferation and cell death. Each of these parameters is strictly regulated by developmental cues to ensure that all organs of a characteristic shape and size are generated. Recently a series of works from drosophila genetics has firestroke the identification of a novel growth control pathway : Hippo pathway. It is composed of the Neurofibromatosis type-2 (NF2) encoded protein Merlin (Mer) and related protein Expanded (Ex), which play a role in cell adhesion and structure; serine/threonine kinase Hippo (Hpo) and Warts (Wts); the adaptor molecule Salvador (Sav), Mob as tumor suppressor (Mats), a regulator of Warts; Yorkie (Yki), a transcriptional coactivator that positively regulates cell growth, survival, and proliferation. Merlin and Expanded control the activation of the Hippo/Salvador complex, which in turn activates the Warts/Mats kinase complex. Warts/Mats kinase phosphorylate and inhibit Yorkie. Mutations in Merlin, Expanded, Hippo, Salvador, Warts, Mats or overexpression of Yorkie result in tissue overgrowth (Edgar, 2006, Cell, 124, 267-273). Mammalian homolog genes in this pathway were identified, but only limited results of them were reported in mice and humans. For example, Lats1 deficient mice develop soft-tissue sarcomas and ovarian stromal cell tumors, and NF2+/- mice showed high incidence of bone tumors, and NF2 conditional mutant mice in schwann cells showed scwannomas phenotype like human disease. Although mammalian compartments of Hippo pathway have been implicated in the regulation of cell proliferation and cell death, the physiological functions of them remain to be determined. (Edgar, 2006, Cell, 124, 267-273; Harvey, 2007, Nat Rev Can, 7, 182-191).

    Recently, our laboratory has generated WW45 knockout mouse to elucidate Hippo pathway in mammals. We found that mutant embryos displayed embryonic lethality and unchecked proliferation with defects in terminal differentiation of epithelial cells. (EMBO J, 2008, 27, 1231-42). Taken together, Hippo pathway appears to suppress cell proliferation and induce apoptosis in drosophila, and its malfunction drives tumourigenesis of multiple organs in mammals. It is our main goal to understand the mechanism and physiology of Hippo pathway in mammalian counterpart.

  • Modern biology is in the era of mouse genetics. Three aspects are of consideration in choosing model organisms for research: power of genetics, relevance to human physiology and pathology, and time of each generation. Even though mice have short generation and wonderfully reflect human biology, poor genetics has hampered their use. However, during last two decades, there had been rapid developments in mouse genetics. Now it is possible to artificially manipulate mice genome in variety of ways: Knock-out (disruption of a gene), conditional knock-out, overexpression of gene, knocking-in wanted DNA segments in the genome. Taking advantage of recent development in mouse genetics, we have engineered various transgenic mice in the mammalian hippo pathway, therefore not confining our research on the cellular level but expanding it to organism level. In addition to cell biological approach, the use of mouse model will provide us better understanding of gene networks controlling cell fate, and ultimately help treat cancer.