-
[show abstract]
[hide abstract]
ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is an inheritable and progressive kidney disease featured by the formation of fluid-filled cysts. In a previous study, transgenic mice overexpressing human PKD2 gene were produced as an ADPKD animal model. To select genes controlled by PKD2, 2DE was performed using kidney tissues of 12 and 18-month-old transgenic mice. The protein localization was detected by immunohistochemistry, and three-dimensional culture was utilized to observe in vitro cystogenesis. As a result, N-myc downstream regulated gene 1 (NDRG1) was chosen as a candidate regulator gene of cystogenesis. NDRG1 is an intracellular protein involved in cellular proliferation and differentiation. This gene was expressed much higher in the kidney of hPKD2 TG mice. Also, the high level of NDRG1 protein was detected in the cyst lining epithelial cells. The hypothesis that PKD2 gene regulates NDRG1 expression was supported, and NDRG1 knockdown resulted in attenuation of cyst growth in vitro. Furthermore, NDRG1 knockdown suppressed cellular growth in mIMCD-3 cells. We found that early growth response 1 (Egr1), a transcription factor that binds to the NDRG1 promoter, was mediated in the NDRG1 expression regulation by PKD2. In this study, we found the novel gene that was involved in cystogenesis, which will provide the new insight in ADPKD.
Proteomics 12/2012; · 4.43 Impact Factor
-
Fengyan Yu,
Yu Jiao,
Yinghua Zhu,
Ying Wang,
Jingde Zhu,
Xiuying Cui,
Yujie Liu,
Yinghua He, Eun-Young Park,
Hongyu Zhang,
Xiaobin Lv,
Kelong Ma,
Fengxi Su,
Jong Hoon Park,
Erwei Song
[show abstract]
[hide abstract]
ABSTRACT: Tumor-initiating cells (T-ICs), a subpopulation of cancer cells with stem cell-like properties, are related to tumor relapse and metastasis. Our previous studies identified a distinct profile of microRNA (miRNA) expression in breast T-ICs (BT-ICs), and the dysregulated miRNAs contribute to the self-renewal and tumorigenesis of these cells. However, the underlying mechanisms for miRNA dysregulation in BT-ICs remain obscure. In the present study, we demonstrated that the expression and function of miR-34c were reduced in the BT-ICs of MCF-7 and SK-3rd cells, a breast cancer cell line enriched for BT-ICs. Ectopic expression of miR-34c reduced the self-renewal of BT-ICs, inhibited epithelial-mesenchymal transition, and suppressed migration of the tumor cells via silencing target gene Notch4. Furthermore, we identified a single hypermethylated CpG site in the promoter region of miR-34c gene that contributed to transcriptional repression of miR-34c in BT-ICs by reducing DNA binding activities of Sp1. Therefore, miR-34c reduction in BT-ICs induced by a single hypermethylated CpG site in the promoter region promotes self-renewal and epithelial-mesenchymal transition of BT-ICs.
Journal of Biological Chemistry 11/2011; 287(1):465-73. · 4.77 Impact Factor
-
Sun Hwa Lee,
Dae Won Kim,
Su Sun Back,
Hyun Sook Hwang, Eun Young Park,
Tae-Cheon Kang,
Oh-Shin Kwon,
Jong Hoon Park,
Sung-Woo Cho,
Kyu Hyung Han,
Jinseu Park,
Won Sik Eum,
Soo Young Choi
[show abstract]
[hide abstract]
ABSTRACT: Annexin-1 (ANX1) is an anti-inflammatory protein as well as an important modulator in inflammation. However, the precise action of ANX1 remains unclear. To elucidate the protective effects of ANX1 on lipopolysaccharide (LPS)-induced murine macrophage Raw 264.7 cells, we constructed a cell-permeable Tat-ANX1 protein. The transduced Tat-ANX1 protein markedly inhibited the expression of cyclooxygenase-2, production of prostaglandin E(2), and generation of pro-inflammatory cytokines in the cells. Furthermore, transduced Tat-ANX1 protein caused a significant reduction in the activation of nuclear factor- kappa B (NF-kB) and mitogen-activated protein kinase (MAPK). The results indicate that Tat-ANX1 inhibits the production of inflammatory response cytokines and enzymes by blocking NF-kB and MAPK. Therefore, Tat-ANX1 protein may be useful as a therapeutic agent against various inflammatory diseases.
BMB reports 07/2011; 44(7):484-9. · 1.72 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Polycystic kidney disease (PKD) is a common genetic disorder in which extensive epithelial-lined cysts develop in the kidneys. In previous studies, abnormalities of polycystin protein and its interacting proteins, as well as primary cilia, have been suggested to play critical roles in the development of renal cysts. However, although several therapeutic targets for PKD have been suggested, no early diagnosis or effective treatments are currently available. Current developments are active for treatment of PKD including inhibitors or antagonists of PPAR-γ, TNF-α, CDK and VEGF. These drugs are potential therapeutic targets in PKD, and need to be determined about pathological functions in human PKD. It has recently been reported that the alteration of epigenetic regulation, as well as gene mutations, may affect the pathogenesis of PKD. In this review, we will discuss recent approaches to PKD therapy. It provides important information regarding potential targets for PKD.
BMB reports 06/2011; 44(6):359-68. · 1.72 Impact Factor
-
Sun A Cho,
Min-Ji Seo,
Je Yeong Ko,
Jung-Hee Shim,
Jin Yoo,
Jung-Hee Kim,
Se Yoon Kim,
Na Kyung Ryu, Eun Young Park,
Han-Woong Lee,
Yeon-Su Lee,
Young Yil Bahk,
Jong-Hoon Park
[show abstract]
[hide abstract]
ABSTRACT: The PC12 is the widely used cell line to study neuronal differentiation. We had extensively investigated the details of protein expression in differentiated PC12 cells by proteomic analysis. The cells were incubated at the presence of nerve growth factor. We had analyzed the expression changes in the differentiating PC12 cells by 2-dimensional electrophoresis and the identification of the proteins using MALDI-TOF MS. By comparing expression pattern in the time course, we identified the candidate genes which are associated with neuronal differentiation. Among these genes, we performed real-time PCR analysis to validate Idh3alpha expression by the time course. To identify the function of Idh3alpha in neuronal differentiation stage, the transfection of Idh3alpha to PC12 cells was performed. As a result, we proved that up-regulation of Idh3alpha causes reduction in neural differentiation of PC12 cells. Based on these data, we suggest that Idh3alpha plays a role to the neuronal differentiation.
BMB reports 05/2010; 43(5):369-74. · 1.72 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation and secretion of fluid and is associated with interstitial inflammation and fibrosis, resulting in the loss of renal function. We previously generated mice overexpressing PKD2, causing progressive cyst development with an inflammatory and fibrotic phenotype in the kidneys.
To profile the gene expression related to inflammation and cystogenesis, microarray analysis was performed with kidney tissue from 6-, 12- and 18-month-old mice. Subsequently, levels and related mechanisms of selected genes, s100a8 and s100a9, were evaluated.
S100a8 and s100a9 was upregulated more than 2-fold and differently expressed in the cystic region. Receptor of advanced glycation end product (RAGE) is a putative cell surface receptor for s100a8/a9. It was expressed in cyst-lining cells and up-regulated pro-inflammatory transcription factor NF-kappaB in transgenic mice. We also confirmed RAGE expression in ADPKD patient kidneys. It was suggested that the signaling related to proliferative cystogenesis through previous reports; therefore, we confirmed that phosphorylated-ERK and cyst formation was reduced by treatment of RAGE-siRNA.
The results may provide important information for the expression of s100a8/a9 and RAGE, linking progressive cystogenesis with inflammation in cystic kidney.
American Journal of Nephrology 01/2010; 32(2):169-78. · 2.54 Impact Factor
-
Eun Young Park,
Young Hoon Sung,
Moon Hee Yang,
Ji Yeun Noh,
So Young Park,
Tae Young Lee,
Yeon Joo Yook,
Kyung Hyun Yoo,
Kyung Jin Roh,
Ingyu Kim,
Young-Hwan Hwang,
Goo Taeg Oh,
Je Kyung Seong,
Curie Ahn,
Han-Woong Lee,
Jong Hoon Park
[show abstract]
[hide abstract]
ABSTRACT: The pathogenic mechanisms of human autosomal dominant polycystic kidney disease (ADPKD) have been well known to include the mutational inactivation of PKD2. Although haploinsufficiency and loss of heterozygosity at the Pkd2 locus can cause cyst formation in mice, polycystin-2 is frequently expressed in the renal cyst of human ADPKD, raising the possibility that deregulated activation of PKD2 may be associated with the cystogenesis of human ADPKD. To determine whether increased PKD2 expression is physiologically pathogenic, we generated PKD2-overexpressing transgenic mice. These mice developed typical renal cysts and an increase of proliferation and apoptosis, which are reflective of the human ADPKD phenotype. These manifestations were first observed at six months, and progressed with age. In addition, we found that ERK activation was induced by PKD2 overexpression via B-Raf signaling, providing a possible molecular mechanism of cystogenesis. In PKD2 transgenic mice, B-Raf/MEK/ERK sequential signaling was up-regulated. Additionally, the transgenic human polycystin-2 partially rescues the lethality of Pkd2 knock-out mice and therefore demonstrates that the transgene generated a functional product. Functional strengthening or deregulated activation of PKD2 may be a direct cause of ADPKD. The present study provides evidence for an in vivo role of overexpressed PKD2 in cyst formation. This transgenic mouse model should provide new insights into the pathogenic mechanism of human ADPKD.
Journal of Biological Chemistry 01/2009; 284(11):7214-22. · 4.77 Impact Factor
-
Young Ju Suh,
Sun A Cho,
Jung Hee Shim,
Yeon Joo Yook,
Kyung Hyun Yoo,
Jung Hee Kim, Eun Young Park,
Ji Yeun Noh,
Seong Ho Lee,
Moon Hee Yang,
Hyo Seok Jeong,
Jong Hoon Park
[show abstract]
[hide abstract]
ABSTRACT: An embryonic stem cell is a powerful tool for investigation of early development in vitro. The study of embryonic stem cell mediated neuronal differentiation allows for improved understanding of the mechanisms involved in embryonic neuronal development. We investigated expression profile changes using time course cDNA microarray to identify clues for the signaling network of neuronal differentiation. For the short time course microarray data, pattern analysis based on the quadratic regression method is an effective approach for identification and classification of a variety of expressed genes that have biological relevance. We studied the expression patterns, at each of 5 stages, after neuronal induction at the mRNA level of embryonic stem cells using the quadratic regression method for pattern analysis. As a result, a total of 316 genes (3.1%) including 166 (1.7%) informative genes in 8 possible expression patterns were identified by pattern analysis. Among the selected genes associated with neurological system, all three genes showing linearly increasing pattern over time, and one gene showing decreasing pattern over time, were verified by RT-PCR. Therefore, an increase in gene expression over time, in a linear pattern, may be associated with embryonic development. The genes: Tcfap2c, Ttr, Wnt3a, Btg2 and Foxk1 detected by pattern analysis, and verified by RT-PCR simultaneously, may be candidate markers associated with the development of the nervous system. Our study shows that pattern analysis, using the quadratic regression method, is very useful for investigation of time course cDNA microarray data. The pattern analysis used in this study has biological significance for the study of embryonic stem cells.
Molecules and Cells 10/2008; 26(4):338-43. · 2.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: ADPKD (Autosomal Dominant Polycystic Kidney Disease) is characterized by the progressive expansion of multiple cystic lesions in the kidneys. ADPKD is caused by mutations in Ed-pl. consider PKD1 and PKD2. Recently a relation between c-myc and the pathogenesis of ADPKD was reported. In addition, c-Myc is a downstream effector of PKD1. To identify the gene regulated by PKD2 and c-Myc, we performed gene expression profiling in PKD2 and c-Myc overexpressing cells using a human 8K cDNA microarray. NCAM (neuronal cell adhesion molecule) levels were significantly reduced in PKD2 overexpressing systems in vitro and in vivo. These results suggest that NCAM is an important molecule in the cystogenesis induced by PKD2 overexpression.
BMB reports 09/2008; 41(8):593-6. · 1.72 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Methamphetamine, a commonly used addictive drug, is a powerful addictive stimulant that dramatically affects the CNS. Repeated METH administration leads to a rewarding effect in a state of addiction that includes sensitization, dependence, and other phenomena. It is well known that susceptibility to the development of addiction is influenced by sources of reinforcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. These behavioral abnormalities reflect neuroadaptive changes in signal transduction function and cellular gene expression produced by repeated drug exposure. To provide a better understanding of addiction and the mechanism of the rewarding effect, it is important to identify related genes. In the present study, we performed gene expression profiling using microarray analysis in a reward effect animal model. We also investigated gene expression in four important regions of the brain, the nucleus accumbens, striatum, hippocampus, and cingulated cortex, and analyzed the data by two clustering methods. Genes related to signaling pathways including G-protein-coupled receptor-related pathways predominated among the identified genes. The genes identified in our study may contribute to the development of a gene modeling network for methamphetamine addiction.
Molecules and Cells 07/2008; 26(2):121-30. · 2.18 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: PCD (programmed cell death) is important mechanism for development, homeostasis and disease. To analyze the gene expression pattern in brain cells undergoing PCD in response to serum deprivation, we analyzed the cDNA microarray consisting of 2,300 genes and 7 housekeeping genes of cortical cells derived from mouse embryonic brain. Cortical cells were induced apoptosis by serum deprivation for 8 hours. We identified 69 up-regulated genes and 21 down-regulated genes in apoptotic cells. Based on the cDNA microarray data four genes were selected and analyzed by RT-PCR and northern blotting. To characterize the role of UNC-51-like kinase (ULK2) gene in PCD, we investigated cell death effect by ULK2. And we examined expression of several genes that related with PCD. Especially GAPDH was increased by ULK2. Theses findings indicated that ULK2 is involved in apoptosis through p53 pathway.
Journal of biochemistry and molecular biology 03/2007; 40(2):277-85. · 2.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 1. The mechanism of stimulation of noradrenaline (NA) release by nicotine (NIC) was investigated in human cerebral cortex slices preloaded with 3H-noradrenaline. 2 NIC (10-1000 micro M) increased 3H-NA release in a concentration-dependent manner. 3. NIC (100 micro M)-evoked 3H-NA release was largely dependent on external Ca2+, and was attenuated by omega-conotoxin GVIA (0.1 micro M) but not by nitrendipine (1 micro M). 4. Tetrodotoxin (1 micro M) and nisoxetine (0.1 micro M) attenuated the NIC (100 micro M)-evoked release of 3H-NA. 5. Mecamylamine (10 micro M), dihydro-beta-erythroidine (10 micro M) and d-tubocurarine (30 micro M), but not alpha-bungarotoxin (alpha-BTX, 0.1 micro M), attenuated the NIC (100 micro M)-evoked release of 3H-NA. 6. NIC (100 micro M)-evoked release of 3H-NA was not affected by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 30 micro M) and D(-)-2-amino-5-phosphonopentanoic acid (D-AP5, 100 micro M), but attenuated by MK-801 (10 micro M). MK-801 (0.1-1000 micro M) displaced the specific binding of 3H-nisoxetine with K(i) values of 91.2 micro M. NIC (100, 300 and 1000 micro M) did not induce 3H-D-aspartate release in human cerebral cortex slices. 7. NIC (100 micro M)-evoked release of 3H-NA was attenuated by 7-nitroindazole (10 micro M), N(G)-nitro-L-arginine methyl ester HCl (L-NAME, 30 micro M), N(G)-monomethyl-L-arginine acetate (L-NMMA, 300 micro M). [(3)H]-NA release induced by NIC (100 micro M) was attenuated by methylene blue (3 micro M) and 1H-[1,2,4]oxadiazole[4,3-alpha]quinoxalin-1-one (ODQ, 10 micro M), and enhanced by zaprinast (30 micro M). 8. In conclusion, NIC stimulates the release of 3H-NA through activation of alpha-BTX-insensitive nicotinic acetylcholine receptors in the human cerebral cortex slices and this action of NIC is associated with modulation of the NO/cGMP pathway.
British Journal of Pharmacology 01/2003; 137(7):1063-70. · 4.41 Impact Factor
