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Lee, Daekee,Yu, Ming,Lee, Eunjung,Kim, Hyunok,Yang, Yanan,Kim, Kyoungmi,Pannicia, Christina,Kurie, Jonathan M.,Threadgill, David W. American Society for Clinical Investigation 2009 The Journal of clinical investigation Vol.119 No.9
<P>Pharmacologic blockade of EGFR or the closely related receptor ERBB2 has modest efficacy against colorectal cancers in the clinic. Although the upregulation of ERBB3, a pseudo-kinase member of the EGFR/ERBB family, is known to contribute to EGFR inhibitor resistance in other cancers, its functions in normal and malignant intestinal epithelium have not been defined. We have shown here that the intestinal epithelium of mice with intestine-specific genetic ablation of Erbb3 exhibits no cytological abnormalities but does exhibit loss of expression of ERBB4 and sensitivity to intestinal damage. By contrast, intestine-specific Erbb3 ablation resulted in almost complete absence of intestinal tumors in the ApcMin mouse model of colon cancer. Unlike nontransformed epithelium lacking ERBB3, intestinal tumors lacking ERBB3 had reduced PI3K/AKT signaling, which led to attenuation of tumorigenesis via a tumor-specific increase in caspase-3-mediated apoptosis. Consistent with the mouse data, which suggest that ERBB3-ERBB4 heterodimers contribute to colon cancer survival, experimentally induced loss of ERBB3 in a KRAS mutant human colon cancer cell line was associated with loss of ERBB4 expression, and siRNA knockdown of either ERBB3 or ERBB4 resulted in elevated levels of apoptosis. These results indicate that the ERBB3 pseudo-kinase has essential roles in supporting intestinal tumorigenesis and suggest that ERBB3 may be a promising target for the treatment of colorectal cancers.</P>
Kwon, Daekee,Kang, Gwang-Sik,Han, Dong Keun,Park, Kwideok,Kim, Jae-Hwan,Lee, Soo-Hong 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.1
Commercially available extracellular matrix (ECM) hydrogel-coated culture plates have been used to study the relationship between the ECM microenvironment and stem cell behavior. However, it is unclear whether ECM-coated dishes mimic the natural ECM microenvironment because the architecture of the ECM is constructed of randomly distributed fibers. The purpose of this study was the production and confirmation of human engineered cell lines stably expressing large ECM proteins such as collagen I/II and fibronectin. First, large (over 10 kb) ECM vectors encoding human collagen I/II and fibronectin were constructed and the circular vectors were linearized. Second, the linear ECM vectors were introduced into immortalized human embryonic kidney cells using various transfection methods. The polyethylenimine and liposome methods showed higher efficiencies than electroporation for transfection of these large vectors. Third, human ECM engineered cells were established by stable integration of the vector into the genomic DNA and resulted in stable overexpression of mRNA and proteins. In summary, human engineered cell lines stably expressing large ECM proteins such as human collagen I/II and fibronectin were successfully prepared, and secretion of the ECM components into the surrounding environment was confirmed by immunocytochemistry. Thus, human ECM engineered cells naturally secreting ECM components could be valuable for studying the relationship between the native ECM microenvironment and stem cell behavior.
Study of epidermal growth factor receptor function using mouse genetics
Lee, Daekee,David Threadgill 이화여자대학교 세포신호전달연구센터 2005 고사리 세포신호전달 심포지움 Vol. No.7
Since the development of transgenic and gene targeting technologies, mouse models have been central to investigating and understanding mammalian gene function. An impressive array of technologies and the completion of the human and mouse genome sequence accelerate our understanding the gene function and their interactions in normal condition as well as in various diseases. Mice heterozygous for the N-ethyl-N-nitrosourea(ENU)-induced Waved-5(Wa5) mutation, isolated in a screen for dominant, visible mutations, exhibit a wavy coat similar to mice homozygous for the recessive Tgfa^(wa1) or Egfr^(wa2) alleles. Wa5 is a new allele of Egfr(Egfr^(Wa5)) containing a mis-sense mutation within the coding region for a highly conserved DFG motif of the tyrosine kinase domain. In vivo analysis of placental development, modification of Apc^(Min) tumorigenesis and levels of EGF-dependent EGFR phosphorylation demonstrates that Egfr^(Wa5) functions as an antimorphic allele, recapitulating many abnormalities associated with reduced EGFR activity. Furthermore, Egfr^(Wa5) enhances Egfr^(wa2) compound or Tgfa^(tm1Dc1) double mutants exposing additional EGFR-dependent phenotypes. In vitro characterization shows that the antimorphic property of Egfr^(Wa5) is caused by a kinase dead receptor acting as a dominant negative. Epiregulin, an epidermal growth factor family member, acts as a local signal mediator and shows dual biological activity, stimulating the proliferation of fibroblasts, hepatocytes, smooth muscle cells, and keratinocytes while inhibiting the growth of several tumor-derived epithelial cell lines. The epiregulin gene(Ereg) is located on mouse chromosome 5 adjacent to three other epidermal growth factor family members, epigen, amphiregulin, and betacellulin. Gene targeting was used to insert a lacZ reporter into the mouse Ereg locus and to ablate its function. Although epiregulin is broadly expressed and regulated both spatially and temporally, Ereg null mice show no overt developmental defects, reproductive abnormalities, or altered liver regeneration. Additionally, in contrast to previous hypotheses, Ereg deficiency does not alter intestinal cancer susceptibility, as assayed in thy Apc^(Min) model, despite showing robust expression in developing tumors. However, Ereg null mice are highly susceptible to cancer-predisposing intestinal damage caused by oral administration of dextran sulfate sodium.
Lin, Jingjing,Lee, Daekee,Choi, Yongwon,Lee, Soo Young American Association for the Advancement of Scienc 2015 Science signaling Vol.8 No.379
<P>The E3 ubiquitin ligase TRAF6 [tumor necrosis factor (TNF) receptor (TNFR)-associated factor 6] and the associated kinase TAK1 [transforming growth factor-β (TGF-β)-activated kinase 1] are key components of the signaling pathways that activate nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) in response to various stimuli. The cytokine RANKL (receptor activator of NF-κB ligand) is essential for the differentiation of bone marrow cells into bone-resorbing osteoclasts through the activation of NF-κB and MAPK. We found that the scaffold protein RACK1 (receptor for activated C kinase 1) selectively mediated the RANKL-dependent activation of p38 MAPK through the TRAF6-TAK1 axis by interacting with the MAPK kinase MKK6 (MAPK kinase kinase 6), which is upstream of p38 MAPK. RACK1 was necessary for the differentiation of bone marrow cells into osteoclasts through the stimulation of p38 MAPK activation. Osteoclast precursors exposed to RANKL exhibited an interaction among RACK1, RANK, TRAF6, TAK1, and the kinase MKK6, thereby leading to the activation of the MKK6-p38 MAPK pathway. Experiments in which RACK1 or TAK1 was knocked down in osteoclast precursors indicated that RACK1 acted as a bridge, bringing MKK6 to the TRAF6-TAK1 complex. Furthermore, local administration of RACK1-specific small interfering RNA (siRNA) into mice calvariae reduced the RANKL-induced bone loss by reducing the numbers of osteoclasts. These findings suggest that RACK1 specifies the RANKL-stimulated activation of p38 MAPK by facilitating the association of MKK6 with TAK1 and may provide a molecular target for a new therapeutic strategy to treat bone diseases.</P>
Isolation and Functional Examination of the Long Non-Coding RNA Redrum
Lee, Yerim,Park, Charny,Lee, Sanghyuk,Lee, Daekee,Kim, Jaesang Korean Society for Molecular and Cellular Biology 2018 Molecules and cells Vol.41 No.2
Here, we report isolation of multiple long non-coding RNAs (lncRNAs) expressed tissue-specifically during murine embryogenesis. One of these, subsequently came to be known as Redrum, is expressed in erythropoietic cells in fetal liver and adult bone marrow. Redrum transcription is also detected during pregnancy in the spleen where extramedullary hematopoiesis takes place. In order to examine the function of Redrum in vivo, we generated a gene-targeted murine model and analyzed its embryonic and adult erythropoiesis. The homozygous mutant embryo showed no apparent deficiency or defect in erythropoiesis. Adult erythropoiesis in bone marrow and in the spleen during pregnancy likewise showed no detectable phenotype as red blood cells matured in normal fashion. The phenotype is in contrast to the reported function of Redrum in vitro, and our observation implies that Redrum plays in vivo an accessory or supplementary role whose loss is compatible with normal erythropoiesis.