• home > Research
  • We are interested in understanding the importance of maintaining the genomic stability to inhibit tumorigenesis and physiology and molecular biology that underlies it. For example, the tumor suppressor RASSF1A is inactivated in a variety of human cancers due to hypermethylation of a CpG island in its promoter. Furthermore, we have identified the roles of RASSF1A in tumorigenesis by inhibiting both APC ligase activity and cyclin ubiquitination during mitosis (Nat Cell Biol, 2004, 6, 129-37), by activating p53 tumor suppressor through a DAXX-HAUSP-MDM2 pathway (EMBO J, 2008, 27, 1863-74). We have also found that Rassf1As destruction is mediated by a F-box protein SKP2 oncoprotein (Oncogene, 2008, 27, 3176-85). We are also studying unidentified mechanisms of the cell cycle regulation by other regulators which are orchestrated with many tumor suppressors and oncoproteins related in cancer pathogenesis in vitro and in vivo.

    The kinase Mst1 and the related protein Mst2 were originally identified as proteins that are activated by certain types of cellular stress and have been shown to participate in a wide range of apoptotic responses. A Drosophila homologue of Mst1/2, Hpo, functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis. Human Mst2 is able to substitute for Hpo in developing Drosophila tissues, providing support for a role of Mst in tumor suppression in mammalian cells. Therefore, given the role of Mst1 as an apoptotic kinase and that of Hpo as a tumor suppressor, we hypothesized that Mst1 is a putative tumor suppressor and have been trying to find a new role of Mst1 as a regulator of cell cycle progression and tumor suppressor in mammals.

  • A new signaling network, known as the Hippo pathway in Drosophila, seems to be a key developmental program in controlling proliferation and apoptosis for proper organ development in Drosophila. Interestingly, the phenotypes of flies with mutations in the Hippo pathway can be rescued with their respective human counterparts, indicating that the Hippo pathway may have an analogous role in development of mammals.

    Using knockout system, we generated mice lacking WW45 (a homolog of Sav in Drosophila) to examine the role of the Hippo pathway in mammals. We found that mutant embryos displayed embryonic lethality and unchecked proliferation with defects in terminal differentiation of epithelial cells. We also revealed the molecular mechanism by which MST1 signaling is spatiotemporally regulated to allow cell-cycle exit and activation of terminal differentiation in epithelial cells (EMBO J, 2008, 27, 1231-42). We also generated various KO and KI mice with defects in Hippo pathway such as WW45-tissue specific knockout mice, and are currently investigating the role of the Hippo pathway further in regulation of organ size and tumorigenesis in mammals.

  • In order to address the molecular functions of YAP (a homolog of Yoki in Drosophila), We are currently performing initial screening of new partners with TAP (Tandem Affinity Purification) and ChIP sequencing. TAP is popularly utilized in yeast to search for new protein complex. We expect similar task can be done with mammalian cells to discover novel transcription factors or other protein complexes that might be involved in functions of YAP within a cell. ChIP sequencing is a massive sequencing technique to determine where in the genome YAP binds within a cell. With ChIP sequencing result, we can discover what genes YAP regulate to exert its function.

  • Previous studies from embryonic stem cells and mouse development have shown that Flk1 (a tyrosine kinase receptor) has crucial roles in forming endothelial cells and blood cells. Also, Flk1 deficient mice die around E9.5 due to the failure of developing blood vessels and yolk sac blood islands. To assess the role of ER71 in hematopoiesis, we have generated ER71 knockout mice, and observed the defects of vasculogenesis and hematopoiesis in mutant. Interestingly, we found that Flk1 transcriptional levels were down-regulated in knockout mice, and were upregulated in response to ER71. Furthermore, we provide compelling evidence that ER71 regulates blood and vessel development and correlates hematopoietic stem cell differentiation. (Cell Stem Cell, 2008, 2, 497-507). We are currently investigating the roles of ER71 in haematopoietic stem cell development by generating the ER71-conditional knock out mice.