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REFERENCE LINKING PLATFORM OF KOREA S&T JOURNALS
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Molecules and Cells
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Journal DOI :
Korea Society for Molecular and Cellular Biology
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Volume & Issues
Volume 38, Issue 12 - Dec 2015
Volume 38, Issue 8 - Aug 2015
Volume 38, Issue 7 - Jul 2015
Volume 38, Issue 6 - Jun 2015
Volume 38, Issue 5 - May 2015
Volume 38, Issue 4 - Apr 2015
Volume 38, Issue 3 - Mar 2015
Volume 38, Issue 2 - Feb 2015
Volume 38, Issue 1 - Jan 2015
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Autophagy in Neurodegenerative Diseases: From Mechanism to Therapeutic Approach
Nah, Jihoon ; Yuan, Junying ; Jung, Yong-Keun ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 381~389
DOI : 10.14348/molcells.2015.0034
Autophagy is a lysosome-dependent intracellular degradation process that allows recycling of cytoplasmic constituents into bioenergetic and biosynthetic materials for maintenance of homeostasis. Since the function of autophagy is particularly important in various stress conditions, perturbation of autophagy can lead to cellular dysfunction and diseases. Accumulation of abnormal protein aggregates, a common cause of neurodegenerative diseases, can be reduced through autophagic degradation. Recent studies have revealed defects in autophagy in most cases of neurodegenerative disorders. Moreover, deregulated excessive autophagy can also cause neurodegeneration. Thus, healthy activation of autophagy is essential for therapeutic approaches in neurodegenerative diseases and many autophagy-regulating compounds are under development for therapeutic purposes. This review describes the overall role of autophagy in neurodegeneration, focusing on various therapeutic strategies for modulating specific stages of autophagy and on the current status of drug development.
The Divergent Roles of STAYGREEN (SGR) Homologs in Chlorophyll Degradation
Sakuraba, Yasuhito ; Park, So-Yon ; Paek, Nam-Chon ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 390~395
DOI : 10.14348/molcells.2015.0039
Degradation of chlorophyll (Chl) by Chl catabolic enzymes (CCEs) causes the loss of green color that typically occurs during senescence of leaves. In addition to CCEs, STAYGREEN1 (SGR1) functions as a key regulator of Chl degradation. Although sgr1 mutants in many plant species exhibit a staygreen phenotype, the biochemical function of the SGR1 protein remains elusive. Many recent studies have examined the physiological and molecular roles of SGR1 and its homologs (SGR2 and SGR-LIKE) in Chl metabolism, finding that these proteins have different roles in different species. In this review, we summarize the recent studies on SGR and discuss the most likely functions of SGR homologs.
3',4',5',5,7-Pentamethoxyflavone Sensitizes Cisplatin-Resistant A549 Cells to Cisplatin by Inhibition of Nrf2 Pathway
Hou, Xiangyu ; Bai, Xupeng ; Gou, Xiaoli ; Zeng, Hang ; Xia, Chen ; Zhuang, Wei ; Chen, Xinmeng ; Zhao, Zhongxiang ; Huang, Min ; Jin, Jing ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 396~401
DOI : 10.14348/molcells.2015.2183
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important redox-sensitive transcription factor that regulates the expression of several cytoprotective genes. More recently, genetic analyses of human tumors have indicated that Nrf2 may cause resistance to chemotherapy. In this study, we found that the expression levels of Nrf2 and its target genes GCLC, HO-1, NQO1 were significantly higher in cisplatin-resistant A549 (A549/CDDP) cells than those in A549 cells, and this resistance was partially reversed by Nrf2 siRNA. 3,4,5,5,7-Pentamethoxyflavone (PMF), a natural flavon extracted from Rutaceae plants, sensitized A549/CDDP to CDDP and substantially induced apoptosis compared with that of CDDP alone treated group, and this reversal effect decreased when Nrf2 was downregulated by siRNA. Mechanistically, PMF reduced Nrf2 expression leading to a reduction of Nrf2 downstream genes, and in contrast, this effect was decreased by blocking Nrf2 with siRNA. Taken together, these results demonstrated that PMF could be used as an effective adjuvant sensitizer to increase the efficacy of chemotherapeutic drugs by downregulating Nrf2 signaling pathway.
N-Acetyl-D-Glucosamine Kinase Is a Component of Nuclear Speckles and Paraspeckles
Sharif, Syeda Ridita ; Lee, HyunSook ; Islam, Md. Ariful ; Seog, Dae-Hyun ; Moon, Il Soo ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 402~408
DOI : 10.14348/molcells.2015.2242
Protein O-GlcNAcylation, dictated by cellular UDP-N-acetylglucosamine (UDP-GlcNAc) levels, plays a crucial role in posttranslational modifications. The enzyme GlcNAc kinase (NAGK, E.C. 184.108.40.206) catalyzes the formation of GlcNAc-6-phosphate, which is a major substrate for the biosynthesis of UDP-GlcNAc. Recent studies have revealed the expression of NAGK in different types of cells especially in neuronal dendrites. Here, by immunocytochemistry (ICC) and immunonucleochemistry (INC) of cultured rat hippocampal neurons, HEK293T and GT1-7 cells, we have showed that NAGK immuno-reactive punctae being present in the nucleoplasm colocalized with small nuclear ribonucleoprotein-associated protein N (snRNPN) and p54NRB, which are speckle and paraspeckle markers, respectively. Furthermore, NAGK IR cluster was also found to be colocalized with GTF2H5 (general transcription factor IIH, polypeptide 5) immuno reactive punctae. In addition, relative localization to the ring of nuclear lamin matrix and to GlcNAc, which is highly enriched in nuclear pore complexes, showed that NAGK surrounds the nucleus at the cytoplasmic face of the nuclear outer membrane. By in situ proximity ligation assay (PLA) we confirmed the colocalization of NAGK with snRNPN in the nucleus and in dendrites, while we also verified the interactions of NAGK with p54NRB, and with GTF2H5 in the nucleus. These associations between NAGK with speckle, paraspeckle and general transcription factor suggest its regulatory roles in gene expression.
Contribution of a Low-Barrier Hydrogen Bond to Catalysis Is Not Significant in Ketosteroid Isomerase
Jang, Do Soo ; Choi, Gildon ; Cha, Hyung Jin ; Shin, Sejeong ; Hong, Bee Hak ; Lee, Hyeong Ju ; Lee, Hee Cheon ; Choi, Kwan Yong ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 409~415
DOI : 10.14348/molcells.2015.2266
Low-barrier hydrogen bonds (LBHBs) have been proposed to have important influences on the enormous reaction rate increases achieved by many enzymes.
-3-ketosteroi isomerase (KSI) catalyzes the allylic isomerization of
-3-ketosteroid to its conjugated
-isomers at a rate that approache the diffusion limit. Tyr14, a catalytic residue of KSI, has been hypothesized to form an LBHB with the oxyanion of a dienolate steroid intermediate generated during the catalysis. The unusual chemical shift of a proton at 16.8 ppm in the nuclear magnetic resonance spectrum has been attributed to an LBHB between Tyr14
and C3-O of equilenin an intermediate analogue, in the active site of D38N KSI. This shift in the spectrum was not observed in Y30F/Y55F/D38N and Y30F/Y55F/Y115F/D38N mutant KSIs when each mutant was complexed with equilenin, suggesting that Tyr14 could not form LBHB with the intermediate analogue in these mutant KSIs. The crystal structure of Y30F/Y55F/Y115F/D38N-equilenin complex revealed that the distance between Tyr14
and C3-O of the bound steroi was within a direct hydrogen bond. The conversion of LBHB to an ordinary hydrogen bond in the mutant KSI reduced the binding affinity for the steroid inhibitors by a factor of 8.1-11. In addition, the absence of LBHB reduced the catalytic activity by only a factor of 1.7-2. These results suggest that the amount of stabilization energy of the reaction intermediate provided by LBHB is small compared with that provided by an ordinary hydrogen bond in KSI.
Nrf2 Expression and Apoptosis in Quercetin-treated Malignant Mesothelioma Cells
Lee, Yoon-Jin ; Lee, David M. ; Lee, Sang-Han ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 416~425
DOI : 10.14348/molcells.2015.2268
NF-E2-related factor 2 (Nrf2), a basic leucine zipper transcription factor, has recently received a great deal of attention as an important molecule that enhances antioxidative defenses and induces resistance to chemotherapy or radiotherapy. In this study, we investigated the apoptosis-inducing and Nrf2- upregulating effects of quercetin on malignant mesothelioma (MM) MSTO-211H and H2452 cells. Quercetin treatment inhibited cell growth and led to upregulation of Nrf2 at both the mRNA and protein levels without altering the ubiquitination and extending the half-life of the Nrf2 protein. Following treatment with quercetin, analyses of the nuclear level of Nrf2, Nrf2 antioxidant response element-binding assay, Nrf2 promoter-luc assay, and RT-PCR toward the Nrf2-regulated gene, heme oxygenase-1, demonstrated that the induced Nrf2 is transcriptionally active. Knockdown of Nrf2 expression with siRNA enhanced cytotoxicity due to the induction of apoptosis, as evidenced by an increase in the level of proapoptotic Bax, a decrease in the level of antiapoptotic Bcl-2 with enhanced cleavage of caspase-3 and PARP proteins, the appearance of a sub-
peak in the flow cytometric assay, and increased percentage of apoptotic propensities in the annexin V binding assay. Effective reversal of apoptosis was observed following pretreatment with the pan-caspase inhibitor Z-VAD. Moreover, Nrf2 knockdown exhibited increased sensitivity to the anticancer drug, cisplatin, presumably by potentiating the oxidative stress induced by cisplatin. Collectively, our data demonstrate the importance of Nrf2 in cytoprotection, survival, and drug resistance with implications for the potential significance of targeting Nrf2 as a promising strategy for overcoming resistance to chemotherapeutics in MM.
In Vivo Expression of the PTB-deleted Odin Mutant Results in Hydrocephalus
Park, Sunjung ; Lee, Haeryung ; Park, Soochul ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 426~431
DOI : 10.14348/molcells.2015.2288
Odin has been implicated in the downstream signaling pathway of receptor tyrosine kinases, such as the epidermal growth factor and Eph receptors. However, the physiologically relevant function of Odin needs to be further determined. In this study, we used Odin heterozygous mice to analyze the Odin expression pattern; the targeted allele contained a
-geo gene trap vector inserted into the 14t intron of the Odin gene. Interestingly, we found that Odin was exclusively expressed in ependymal cells along the brain ventricles. In particular, Odin was highly expressed in the subcommissural organ, a small ependymal glandular tissue. However, we did not observe any morphological abnormalities in the brain ventricles or ependymal cells of Odin null-mutant mice. We also generated BAC transgenic mice that expressed the PTB-deleted Odin (dPTB) after a floxed GFP-STOP cassette was excised by tissue-specific Cre expression. Strikingly, Odin-dPTB expression played a causative role in the development of the hydrocephalic phenotype, primarily in the midbrain. In addition, Odin-dPTB expression disrupted proper development of the subcommissural organ and interfered with ependymal cell maturation in the cerebral aqueduct. Taken together, our findings strongly suggest that Odin plays a role in the differentiation of ependymal cells during early postnatal brain development.
Overexpression of Long Non-Coding RNA HOTAIR Promotes Tumor Growth and Metastasis in Human Osteosarcoma
Wang, Bo ; Su, Yun ; Yang, Qun ; Lv, Decheng ; Zhang, Weiguo ; Tang, Kai ; Wang, Hong ; Zhang, Rui ; Liu, Yang ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 432~440
DOI : 10.14348/molcells.2015.2327
Human osteosarcoma usually presented a high tendency to metastatic spread and caused poor outcomes, however, the underlying mechanism was still largely unknown. In the present study, using a series of in vitro experiments and an animal model, we investigated the roles of HOX antisense intergenic RNA (HOTAIR) during the proliferation and invasion of osteosarcoma. According with our results, HOTAIR was commonly overexpressed in osteosarcoma, which significantly correlated with advanced tumor stage, highly histological grade and poor prognosis. In vitro and in vivo experiments demonstrated that knockdown of HOTAIR could notably suppress cellular proliferation, inhibit invasion and decrease the secretion of MMP2 and MMP9 in osteosarcoma. Collectively, our results suggested that HOTAIR might be a potent therapeutic target for osteosarcoma.
STING Negatively Regulates Double-Stranded DNA-Activated JAK1-STAT1 Signaling via SHP-1/2 in B Cells
Dong, Guanjun ; You, Ming ; Ding, Liang ; Fan, Hongye ; Liu, Fei ; Ren, Deshan ; Hou, Yayi ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 441~451
DOI : 10.14348/molcells.2015.2359
Recognition of cytosolic DNA initiates a series of innate immune responses by inducing IFN-I production and subsequent triggering JAK1-STAT1 signaling which plays critical roles in the pathogenesis of infection, inflammation and autoimmune diseases through promoting B cell activation and antibody responses. The stimulator of interferon genes protein (STING) has been demonstrated to be a critical hub of type I IFN induction in cytosolic DNA-sensing pathways. However, it still remains unknown whether cytosolic DNA can directly activate the JAK1-STAT1 signaling or not. And the role of STING is also unclear in this response. In the present study, we found that dsDNA directly triggered the JAK1-STAT1 signaling by inducing phosphorylation of the Lyn kinase. Moreover, this response is not dependent on type I IFN receptors. Interestingly, STING could inhibit dsDNA-triggered activation of JAK1-STAT1 signaling by inducing SHP-1 and SHP-2 phosphorylation. In addition, compared with normal B cells, the expression of STING was significantly lower and the phosphorylation level of JAK1 was significantly higher in B cells from MRL/lpr lupus-prone mice, highlighting the close association between STING low-expression and JAK1-STAT1 signaling activation in B cells in autoimmune diseases. Our data provide a molecular insight into the novel role of STING in dsDNA-mediated inflammatory disorders.
Increased Methylation of Interleukin 6 Gene Is Associated with Obesity in Korean Women
Na, Yeon Kyung ; Hong, Hae Sook ; Lee, Won Kee ; Kim, Young Hun ; Kim, Dong Sun ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 452~456
DOI : 10.14348/molcells.2015.0005
Obesity is the fifth leading risk for death globally, and a significant challenge to global health. It is a common, complex, non-malignant disease and develops due to interactions between the genes and the environment. DNA methylation can act as a downstream effector of environmental signals; analysis of this process therefore holds substantial promise for identifying mechanisms through which genetic and environmental factors jointly contribute to disease risk. To assess the effects of excessive weight and obesity on gene-specific methylation levels of promoter regions, we determined the methylation status of four genes involved in inflammation and oxidative stress [interleukin 6 (IL6), tumor necrosis factor
), mitochondrial transcription factor A (TFAM), and glucose transport 4 (GLUT4)] in blood cell-derived DNA from healthy women volunteers with a range of body mass indices (BMIs) by methylation-specific PCR. Interestingly, the samples from obese individuals (
) showed significantly increased hypermethylation for IL6 gene compared to normal weight (
) and overweight sample (
) (P = 0.034 and P = 0.026). However there was no statistically significant difference in promoter methylation of the other 3 genes between each group. These findings suggest that aberrant DNA methylation of IL6 gene promoter may play an important role in the etiology and pathogenesis of obesity and IL6 methylation could be used as molecular biomarker for obesity risk assessment. Further studies are required to elucidate the potential mechanisms underlying this relationship.
Cell Proliferation and Motility Are Inhibited by G1 Phase Arrest in 15-kDa Selenoprotein-Deficient Chang Liver Cells
Bang, Jeyoung ; Huh, Jang Hoe ; Na, Ji-Woon ; Lu, Qiao ; Carlson, Bradley A. ; Tobe, Ryuta ; Tsuji, Petra A. ; Gladyshev, Vadim N. ; Hatfield, Dolph L. ; Lee, Byeong Jae ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 457~465
DOI : 10.14348/molcells.2015.0007
The 15-kDa selenoprotein (Sep15) is a selenoprotein residing in the lumen of the endoplasmic reticulum (ER) and implicated in quality control of protein folding. Herein, we established an inducible RNAi cell line that targets Sep15 mRNA in Chang liver cells. RNAi-induced Sep15 deficiency led to inhibition of cell proliferation, whereas cell growth was resumed after removal of the knockdown inducer. Sep15-deficient cells were arrested at the G1 phase by upregulating p21 and p27, and these cells were also characterized by ER stress. In addition, Sep15 deficiency led to the relocation of focal adhesions to the periphery of the cell basement and to the decrease of the migratory and invasive ability. All these changes were reversible depending on Sep15 status. Rescuing the knockdown state by expressing a silent mutant Sep15 mRNA that is resistant to siRNA also reversed the phenotypic changes. Our results suggest that SEP15 plays important roles in the regulation of the G1 phase during the cell cycle as well as in cell motility in Chang liver cells, and that this selenoprotein offers a novel functional link between the cell cycle and cell motility.
Whole-Genome Resequencing Analysis of Hanwoo and Yanbian Cattle to Identify Genome-Wide SNPs and Signatures of Selection
Choi, Jung-Woo ; Choi, Bong-Hwan ; Lee, Seung-Hwan ; Lee, Seung-Soo ; Kim, Hyeong-Cheol ; Yu, Dayeong ; Chung, Won-Hyong ; Lee, Kyung-Tai ; Chai, Han-Ha ; Cho, Yong-Min ; Lim, Dajeong ;
Molecules and Cells, volume 38, issue 5, 2015, Pages 466~473
DOI : 10.14348/molcells.2015.0019
Over the last 30 years, Hanwoo has been selectively bred to improve economically important traits. Hanwoo is currently the representative Korean native beef cattle breed, and it is believed that it shared an ancestor with a Chinese breed, Yanbian cattle, until the last century. However, these two breeds have experienced different selection pressures during recent decades. Here, we whole-genome sequenced 10 animals each of Hanwoo and Yanbian cattle (20 total) using the Illumina HiSeq 2000 sequencer. A total of approximately 3.12 and 3.07 billion sequence reads were mapped to the bovine reference sequence assembly (UMD 3.1) at an average of approximately 10.71- and 10.53-fold coverage for Hanwoo and Yanbian cattle, respectively. A total of 17,936,399 single nucleotide polymorphisms (SNPs) were yielded, of which 22.3% were found to be novel. By annotating the SNPs, we further retrieved numerous nonsynonymous SNPs that may be associated with traits of interest in cattle. Furthermore, we performed whole-genome screening to detect signatures of selection throughout the genome. We located several promising selective sweeps that are potentially responsible for economically important traits in cattle; the PPP1R12A gene is an example of a gene that potentially affects intramuscular fat content. These discoveries provide valuable genomic information regarding potential genomic markers that could predict traits of interest for breeding programs of these cattle breeds.