| People in our laboratory are interested in three major questions;|
How protein degradation is regulated in lymphocytes, cancer, stem cells, and iPS cells, and what causes recurrent spontaneous abortion (RSA) and polycystic ovarian syndrome (PCOS). In addition, we are investigating the biological roles of oncogenes and tumor suppressor genes including lgl oncogene family members. We use a combination of molecular and genetic approaches as well as immunological approach to investigate these questions.
Overview of Laboratory Projects
1. Areas of Research
Ⅰ. Deubiquitinating Enzymes (DUBs)
Hematopoietic cell growth and differentiation are regulated by cytokines that induce the expression of specific target genes. Some genes directly control mitogenesis. Others regulate intracellular proteolysis, allowing a cell to rapidly switch from one physiologic state to another. Ubiquitin mediated proteolysis is an important mechanism for regulating cellular progresses in all eukaryotic cells. Polybiquitinated proteins are recognized and degraded by the proteasome, a multi-subunit protein degradation complex. Recently, this mechanism has been implicated in a diverse assortment of processes, including cell cycle regulation, transcriptional activation, and antigen presentation.
A large superfamily of genes encoding deubiquitinating enzymes (ubps), has recently been identified. Ubps are ubiquitin-specific thiolproteases that cleave linear ubiquitin precursor proteins or post-translationally modified proteins containing isopeptide ubiquitin conjugates. The cellular function of the ubps is not well understood. Interestingly, ubps vary in length and structural complexitiy, suggesting considerable function diversity. Sequence comparison reveals three conserved domains that serve as the active site for the enzyme.
DUB-1 and DUB-2 are deubiquitinating enzymes isolated by screening a murine genomic library and have a simple two exon structure. DUB-1 is an immediate early gene specifically induced by IL-3, and is expressed only in hematopoietic B-cell progenitor cells. DUB-2 is a T-cell specific immediate-early gene induced by IL-2. Therefore, characterizing and understanding of the DUB enzymes is critical for the understanding of their role in growth regulatory differentiation and mitogenic processes in hematopoietic cells. Given the specificity of DUB-1 for hematopoietic B-cell progenitor cells and DUB-2 specificity for T-cells, this research project will be extremely relevant to the understanding of leukomogenesis.
Ⅱ. Recurrent Spontaneous Abortion (RSA) & Polycystic Ovarian Syndrome (PCOS)
Recurrent spontaneous abortion (RSA), defined as the occurrence of a clinically detectable pregnancy loss within 20 weeks' gestation on 3 or more occasions, takes place as many as 1 in 125 pregnancies. The majority of these abortions occur between 5 and 8 weeks' gestation. However, in as many as 40-60% of these cases, the cause remains unknown. This research project will be involved in identifying and cloning the factor(s) that are less expressed or more expressed in RSA patients.
The scientific and clinical benefits of this effort will ultimately enable the physician to more effectively address the uncertainty that confronts patients experiencing habitual abortion. Eventually, patients possessing mutations in these genes will be screened for both normal pregnancy and pregnancy through in vitro fertilization (IVF) and embryo transfer (ET) in order to protect them from habitual abortion.
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, affecting 5-10% of women in reproductive age, and is characterized by hyperandrogenism, chronic anovulatory cycle, and oligomenorrhea or amenorrhea. Serum luteinizing hormone (LH) hypersecretion, insulin resistance, and compensatory hyperinsulinemia are common biochemical features of PCOS and at least 50% of the PCOS women are insulin resistant when compared with age- and weight-matched controls.
We identified for the first time PCOS-associated proteins in follicular fluid of PCOS patients using proteomic tools and confirmed by Western blot analysis. We are going to determine whether these proteins are involved in the pathogenesis of PCOS.
Ⅲ. Recessive Oncogene lgl Family Members
In order to understand the mechanisms of cancer development and metastasis, researchers have been trying to identify and study tumor suppressor genes and protp-oncogenes in various living organisms. The lethal (2) giant larvae (l(2)gl), the first recessive oncogene found in Drosophila, has been known that homozygous mutations at this locus lead to the development of transplantable neoplasms. The l(2)gl homologues in other organisms have been identified. Including Saccharomyces cerevisiae, Caenorhabditis elegans, mouse mgl-l, and human hugl.
Since there are conserved structure of genes, the similarity of cellular processes, and functional conservation of proto-oncogenes and tumor suppressor genes among different species, it is possible that delineating the mechanisms of cancer development and metastasis in lower animals such as mice and rats can directly contribute to the understanding of them in human.
2. Research Grants
Ⅰ. BK21 Plus (Supported by Korea Research Foundation: 2013.09 - 2020.08)
Ⅱ. RPL (Supported by Ministry of Health & Welfare: 2018.04 - 2020.12)
Ⅲ. Basic Science Research Program (Supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education: 2019.06 - 2028.02)
Ⅰ. The Role of Deubiquitinating Enzymes in Lymphocyte Signal Transduction
(Supported by Korea Research Foundation: 1999.12 - 2000.11)
Ⅱ. Deubiquitinating Enzyme Studies on Leukemia Development
(Supported by Korea Research Foundation: 2000.09 - 2001.08)
Ⅲ. Improvment of Preimplantation Embryo Development by the Regulation of Protein Degradation
(Supported by Ministry of Health & Welfare: 2002.07 - 2004.04)
IV. Development of Novel Technologies in Reproductive Medicine: Ovum Bank, Oocyte Microsurgery, Innovative Embryo Culture System and Specific Cell Lineage Production Using Embryonic Stem Cells
(Supported by Korea Science and Engineering Foundation: 1999.09 - 2004.08)
V. Mass Production of the Targeted ES Clones and In Vivo Functional Analyses of the DUB Genes
(Supported by Korea Institute of S&T Evaluation and Planning: 2002.10 - 2004.03)
VI. Genome Research Center for Reproductive Medicine and Infertility
(Supported by Ministry of Health & Welfare: 2001.12 - 2010.11)
VII. Development of Protein Chip System for Library Screening of Cell Membrane Receptor Antagonists (Supported by Korea Institute of S&T Evaluation and Planning: 2004.08 - 2012.07)
VIII. Mgl-1 (Supported by Ministry of Health & Welfare: 2011.05 - 2014.04)
IV. HAUSP (Supported by Korea Research Foundation: 2010.05 - 2013.04)
X. Stem Cell (Supported by Korea Research Foundation: 2011.05 - 2014.04)
XI. DUB-Bcl2 (Supported by Korea Research Foundation: 2013.11 - 2016.10)
XⅡ. DUB - DNA Repair (Supported by Korea Research Foundation: 2016.06 - 2019.05)
XⅢ. POF (Supported by Ministry of Environment: 2016.04- 2019.12)