Geun Taek Lee

Bio: Geun Taek Lee is an academic researcher from Rutgers University. The author has contributed to research in topics: Prostate cancer & Bone morphogenetic protein. The author has an hindex of 22, co-authored 52 publications receiving 1611 citations. Previous affiliations of Geun Taek Lee include Yonsei University & Soonchunhyang University.

Role of Reactive Oxygen Species in TGF-β1-Induced Mitogen-Activated Protein Kinase Activation and Epithelial-Mesenchymal Transition in Renal Tubular Epithelial Cells

Abstract: Epithelial-mesenchymal transition (EMT) plays an important role in renal tubulointerstitial fibrosis and TGF-beta1 is the key inducer of EMT. Phosphorylation of Smad proteins and/or mitogen-activated protein kinases (MAPK) is required for TGF-beta1-induced EMT. Because reactive oxygen species (ROS) are involved in TGF-beta1 signaling and are upstream signaling molecules to MAPK, this study examined the role of ROS in TGF-beta1-induced MAPK activation and EMT in rat proximal tubular epithelial cells. Growth-arrested and synchronized NRK-52E cells were stimulated with TGF-beta1 (0.2 to 20 ng/ml) or H(2)O(2) (1 to 500 microM) in the presence or absence of antioxidants (N-acetylcysteine or catalase), inhibitors of NADPH oxidase (diphenyleneiodonium and apocynin), mitochondrial electron transfer chain subunit I (rotenone), and MAPK (PD 98059, an MEK [MAP kinase/ERK kinase] inhibitor, or p38 MAPK inhibitor) for up to 96 h. TGF-beta1 increased dichlorofluorescein-sensitive cellular ROS, phosphorylated Smad 2, p38 MAPK, extracellular signal-regulated kinases (ERK)1/2, alpha-smooth muscle actin (alpha-SMA) expression, and fibronectin secretion and decreased E-cadherin expression. Antioxidants effectively inhibited TGF-beta1-induced cellular ROS, phosphorylation of Smad 2, p38 MAPK, and ERK, and EMT. H(2)O(2) reproduced all of the effects of TGF-beta1 with the exception of Smad 2 phosphorylation. Chemical inhibition of ERK but not p38 MAPK inhibited TGF-beta1-induced Smad 2 phosphorylation, and both MAPK inhibitors inhibited TGF-beta1- and H(2)O(2)-induced EMT. Diphenyleneiodonium, apocynin, and rotenone also significantly inhibited TGF-beta1-induced ROS. Thus, this data suggest that ROS play an important role in TGF-beta1-induced EMT primarily through activation of MAPK and subsequently through ERK-directed activation of Smad pathway in proximal tubular epithelial cells.

Irreversible inactivation of glutathione peroxidase 1 and reversible inactivation of peroxiredoxin II by H2O2 in red blood cells.

Abstract: Catalase, glutathione peroxidase1 (GPx1), and peroxiredoxin (Prx) II are the principal enzymes responsible for peroxide elimination in RBC. We have now evaluated the relative roles of these enzymes by studying inactivation of GPx1 and Prx II in human RBCs. Mass spectrometry revealed that treatment of GPx1 with H(2)O(2) converts the selenocysteine residue at its active site to dehydroalanine (DHA). We developed a blot method for detection of DHA-containing proteins, with which we observed that the amount of DHA-containing GPx1 increases with increasing RBC density, which is correlated with increasing RBC age. Given that the conversion of selenocysteine to DHA is irreversible, the content of DHA-GPx1 in each RBC likely reflects total oxidative stress experienced by the cell during its lifetime. Prx II is inactivated by occasional hyperoxidation of its catalytic cysteine to cysteine sulfinic acid during catalysis. We believe that the activity of sulfiredoxin in RBCs is sufficient to counteract the hyperoxidation of Prx II that occurs in the presence of the basal level of H(2)O(2) flux resulting from hemoglobin autoxidation. If the H(2)O(2) flux is increased above the basal level, however, the sulfinic Prx II begins to accumulate. In the presence of an increased H(2)O(2) flux, inhibition of catalase accelerated the accumulation of sulfinic Prx II, indicative of the protective role of catalase.

Effect of bone morphogenetic protein‐6 on macrophages

Abstract: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-beta superfamily which regulates bone formation, haematopoiesis and development. While TGF-beta is known to be a negative regulator of the immune system, the effect of BMPs on the immune system is largely unknown. Herein, the effect of BMP-6 on the innate immune system was investigated using the murine macrophage cell line RAW 264.7. BMP-6 altered cellular morphology, inhibited cellular proliferation, increased the fraction of subG(1) phase cells, and decreased the fraction of cells in the S and G(2)M phases, without changing the percentage of apoptotic cells. In addition, BMP-6 induced expression of pro-inflammatory inducible nitric oxide synthase (iNOS) and the cytokine tumour necrosis factor (TNF)-alpha. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated the expression of all three known type II BMP receptors [BMP-RII, activin (Act)-RIIA and Act-RIIB] and two of the three known type I receptors [activin receptor-like kinase 2 (ALK2) and ALK3]. Over-expression as well as knock-down studies using short hairpin RNA (shRNA) demonstrated that BMP-RII, ALK2 and ALK3 are the functional BMP-6 receptors in macrophages. Finally, the effect of BMP-6 was confirmed in murine peritoneal macrophages and the THP-1 human monocyte cell line. Taken together, these results demonstrate that BMP-6 regulates the proliferation and gene expression profile of macrophages.

BMP-6 in Renal Cell Carcinoma Promotes Tumor Proliferation through IL-10–Dependent M2 Polarization of Tumor-Associated Macrophages

Abstract: Dysregulated bone morphogenetic proteins (BMP) may contribute to the development and progression of renal cell carcinoma (RCC). Herein, we report that BMP-6 promotes the growth of RCC by interleukin (IL)-10-mediated M2 polarization of tumor-associated macrophages (TAM). BMP-6-mediated IL-10 expression in macrophages required Smad5 and STAT3. In human RCC specimens, the three-marker signature BMP-6/IL-10/CD68 was associated with a poor prognosis. Furthermore, patients with elevated IL-10 serum levels had worse outcome after surgery. Together, our results suggest that BMP-6/macrophage/IL-10 regulates M2 polarization of TAMs in RCC.

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Abstract: For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

TGF-beta and epithelial-to-mesenchymal transitions.

Abstract: Remarkable phenotype plasticity of epithelial cells underlies morphogenesis, epithelial repair and tumor invasiveness. Detailed understanding of the contextual cues and molecular mediators that control epithelial plasticity will be required in order to develop viable therapeutic approaches targeting epithelial-to-mesenchymal transition (EMT), an advanced manifestation of epithelial plasticity. Members of the transforming growth factor (TGF-β) family of growth factors can initiate and maintain EMT in a variety of biological systems and pathophysiological context by activating major signaling pathways and transcriptional regulators integrated in extensive signaling networks. Here we will review the distinct physiological contexts of EMT and the underlying molecular signaling networks controlled by TGF-β.

Chronic inflammation and cytokines in the tumor microenvironment.

Abstract: Acute inflammation is a response to an alteration induced by a pathogen or a physical or chemical insult, which functions to eliminate the source of the damage and restore homeostasis to the affected tissue. However, chronic inflammation triggers cellular events that can promote malignant transformation of cells and carcinogenesis. Several inflammatory mediators, such as TNF-α, IL-6, TGF-β, and IL-10, have been shown to participate in both the initiation and progression of cancer. In this review, we explore the role of these cytokines in important events of carcinogenesis, such as their capacity to generate reactive oxygen and nitrogen species, their potential mutagenic effect, and their involvement in mechanisms for epithelial mesenchymal transition, angiogenesis, and metastasis. Finally, we will provide an in-depth analysis of the participation of these cytokines in two types of cancer attributable to chronic inflammatory disease: colitis-associated colorectal cancer and cholangiocarcinoma.