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  • MinireviewJuly 31, 2017

    57 283 4535
    Abstract

    Abstract : Proteolysis in eukaryotic cells is mainly mediated by the ubiquitin (Ub)-proteasome system (UPS) and the autophagylysosome system (hereafter autophagy). The UPS is a selective proteolytic system in which substrates are recognized and tagged with ubiquitin for processive degradation by the proteasome. Autophagy is a bulk degradative system that uses lysosomal hydrolases to degrade proteins as well as various other cellular constituents. Since the inception of their discoveries, the UPS and autophagy were thought to be independent of each other in components, action mechanisms, and substrate selectivity. Recent studies suggest that cells operate a single proteolytic network comprising of the UPS and autophagy that share notable similarity in many aspects and functionally cooperate with each other to maintain proteostasis. In this review, we discuss the mechanisms underlying the crosstalk and interplay between the UPS and autophagy, with an emphasis on substrate selectivity and compensatory regulation under cellular stresses.

  • MinireviewJuly 31, 2017

    7 227 3279

    Implications of Circadian Rhythm in Dopamine and Mood Regulation

    Jeongah Kim, Sangwon Jang, Han Kyoung Choe, Sooyoung Chung, Gi Hoon Son, and Kyungjin Kim

    Mol. Cells 2017; 40(7): 450-456 https://doi.org/10.14348/molcells.2017.0065
    Abstract

    Abstract : Mammalian physiology and behavior are regulated by an internal time-keeping system, referred to as circadian rhythm. The circadian timing system has a hierarchical organization composed of the master clock in the suprachiasmatic nucleus (SCN) and local clocks in extra-SCN brain regions and peripheral organs. The circadian clock molecular mechanism involves a network of transcription-translation feedback loops. In addition to the clinical association between circadian rhythm disruption and mood disorders, recent studies have suggested a molecular link between mood regulation and circadian rhythm. Specifically, genetic deletion of the circadian nuclear receptor Rev-erbα induces mania-like behavior caused by increased midbrain dopaminergic (DAergic) tone at dusk. The association between circadian rhythm and emotion-related behaviors can be applied to pathological conditions, including neurodegenerative diseases. In Parkinson’s disease (PD), DAergic neurons in the substantia nigra pars compacta progressively degenerate leading to motor dysfunction. Patients with PD also exhibit non-motor symptoms, including sleep disorder and neuropsychiatric disorders. Thus, it is important to understand the mechanisms that link the molecular circadian clock and brain machinery in the regulation of emotional behaviors and related midbrain DAergic neuronal circuits in healthy and pathological states. This review summarizes the current literature regarding the association between circadian rhythm and mood regulation from a chronobiological perspective, and may provide insight into therapeutic approaches to target psychiatric symptoms in neurodegenerative diseases involving circadian rhythm dysfunction.

  • ArticleJuly 31, 2017

    3 93 1460
    Abstract

    Abstract : Streptozotocin (STZ)-induced murine models of type 1 diabetes have been used to examine ER stress during pancreatic β-cell apoptosis, as this ER stress plays important roles in the pathogenesis and development of the disease. However, the mechanisms linking type 1 diabetes to the ER stress-modulating anti-diabetic signaling pathway remain to be addressed, though it was recently established that ERK5 (Extracellular-signal-regulated kinase 5) contributes to the pathogeneses of diabetic complications. This study was undertaken to explore the mechanism whereby ERK5 inhibition instigates pancreatic β-cell apoptosis via an ER stress-dependent signaling pathway. STZ-induced diabetic WT and CHOP deficient mice were i.p. injected every 2 days for 6 days under BIX02189 (a specific ERK5 inhibitor) treatment in order to evaluate the role of ERK5. Hyperglycemia was exacerbated by co-treating C57BL/6J mice with STZ and BIX02189 as compared with mice administered with STZ alone. In addition, immunoblotting data revealed that ERK5 inhibition activated the unfolded protein response pathway accompanying apoptotic events, such as, PARP-1 and caspase-3 cleavage. Interestingly, ERK5 inhibition-induced exacerbation of pancreatic β-cell apoptosis was inhibited in CHOP deficient mice. Moreover, transduction of adenovirus encoding an active mutant form of MEK5α, an upstream kinase of ERK5, inhibited STZ-induced unfolded protein responses and β-cell apoptosis. These results suggest that ERK5 protects against STZ-induced pancreatic β-cell apoptosis and hyperglycemia by interrupting the ER stress-mediated apoptotic pathway.

  • ArticleJuly 31, 2017

    2 129 1084

    Assessment of the Therapeutic Potential of Persimmon Leaf Extract on Prediabetic Subjects

    Mohd M. Khan, Bao Quoc Tran, Yoon-Jin Jang, Soo-Hyun Park, William E. Fondrie, Khadiza Chowdhury, Sung Hwan Yoon, David R. Goodlett, Soo-Wan Chae, Han-Jung Chae, Seung-Young Seo, and Young Ah Goo

    Mol. Cells 2017; 40(7): 466-475 https://doi.org/10.14348/molcells.2017.2298
    Abstract

    Abstract : Dietary supplements have exhibited myriads of positive health effects on human health conditions and with the advent of new technological advances, including in the fields of proteomics, genomics, and metabolomics, biological and pharmacological activities of dietary supplements are being evaluated for their ameliorative effects in human ailments. Recent interests in understanding and discovering the molecular targets of phytochemical-gene-protein-metabolite dynamics resulted in discovery of a few protein signature candidates that could potentially be used to assess the effects of dietary supplements on human health. Persimmon (Diospyros kaki) is a folk medicine, commonly used as dietary supplement in China, Japan, and South Korea, owing to its different beneficial health effects including anti-diabetic implications. However, neither mechanism of action nor molecular biomarkers have been discovered that could either validate or be used to evaluate effects of persimmon on human health. In present study, Mass Spectrometry (MS)-based proteomic studies were accomplished to discover proteomic molecular signatures that could be used to understand therapeutic potentials of persimmon leaf extract (PLE) in diabetes amelioration. Saliva, serum, and urine samples were analyzed and we propose that salivary proteins can be used for evaluating treatment effectiveness and in improving patient compliance. The present discovery proteomics study demonstrates that salivary proteomic profile changes were found as a result of PLE treatment in prediabetic subjects that could specifically be used as potential protein signature candidates.

  • ArticleJuly 31, 2017

    9 104 1697

    O-GlcNAcylation of NF-κB Promotes Lung Metastasis of Cervical Cancer Cells via Upregulation of CXCR4 Expression

    Akhtar Ali, Sung Hwan Kim, Min Jun Kim, Mee Young Choi, Sang Soo Kang, Gyeong Jae Cho, Yoon Sook Kim, Jun-Young Choi, and Wan Sung Choi

    Mol. Cells 2017; 40(7): 476-484 https://doi.org/10.14348/molcells.2017.2309
    Abstract

    Abstract : C-X-C chemokine receptor 4 (CXCR4) stimulates cancer metastasis. NF-κB regulates CXCR4 expression in cancer cells, and O-GlcNAc modification of NF-κB promotes its transcriptional activity. Here, we determined whether CXCR4 expression is affected by O-GlcNAcylation of NF-κB in lung metastasis of cervical cancer. We found elevated levels of O-linked-N-actylglucosamine transferase (OGT) and O-GlcNAcylation in cervical cancer cells compared to those in non-malignant epithelial cells and detected increased expression of NF-κB p65 (p65) and CXCR4 in cervical cancer cells. Knockdown of OGT inhibited the O-GlcNAcylation of p65 and decreased CXCR4 expression levels in HeLa cells. Thiamet G treatment increased O-GlcNAcylated p65, which subsequently enhanced CXCR4 expression levels. Inhibition of O-GlcNAcylation by 6-Diazo-5-oxo-L-norleucine (DON) treatment decreased p65 activation, eventually inhibiting CXCR4 expression in HeLa cells. Lung tissues from mice engrafted with OGT-knockdown HeLa cells (shOGT) exhibited lower expression of Ki-67 and HPV E6 and E7 oncogenes compared to lung tissues from mice engrafted with control HeLa cells (shCTL). In addition, lung tissues from mice engrafted with shOGT cells exhibited lower p65 and CXCR4 immunoreactivity compared to tissues from mice engrafted with shCTL cells. Taken together, our data suggest that p65 O-GlcNAcylation promotes lung metastasis of cervical cancer cells by activating CXCR4 expression.

  • ArticleJuly 31, 2017

    1 76 855

    Oleanolic Acid Promotes Neuronal Differentiation and Histone Deacetylase 5 Phosphorylation in Rat Hippocampal Neurons

    Hye-Ryeong Jo, Sung Eun Wang, Yong-Seok Kim, Chang Ho Lee, and Hyeon Son

    Mol. Cells 2017; 40(7): 485-494 https://doi.org/10.14348/molcells.2017.0034
    Abstract

    Abstract : Oleanolic acid (OA) has neurotrophic effects on neurons, although its use as a neurological drug requires further research. In the present study, we investigated the effects of OA and OA derivatives on the neuronal differentiation of rat hippocampal neural progenitor cells. In addition, we investigated whether the class II histone deacetylase (HDAC) 5 mediates the gene expression induced by OA. We found that OA and OA derivatives induced the formation of neurite spines and the expression of synapse-related molecules. OA and OA derivatives stimulated HDAC5 phosphorylation, and concurrently the nuclear export of HDCA5 and the expression of HDAC5 target genes, indicating that OA and OA derivatives induce neural differentiation and synapse formation via a pathway that involves HDAC5 phosphorylation.

  • ArticleJuly 31, 2017

    0 86 924

    5-Hydroxytryptamine 6 Receptor (5-HT6R)-Mediated Morphological Changes via RhoA-Dependent Pathways

    Md. Ataur Rahman, Hanna Kim, Kang Ho Lee, Hyung-Mun Yun, Jung-Hwa Hong, Youngjae Kim, Hyunah Choo, Mikyoung Park, and Hyewhon Rhim

    Mol. Cells 2017; 40(7): 495-502 https://doi.org/10.14348/molcells.2017.0080
    Abstract

    Abstract : The 5-HT6R has been considered as an attractive therapeutic target in the brain due to its exclusive expression in the brain. However, the mechanistic linkage between 5-HT6Rs and brain functions remains poorly understood. Here, we examined the effects of 5-HT6R-mediated cell morphological changes using immunocytochemistry, Western blot, and live-cell imaging assays. Our results showed that the activation of 5-HT6Rs caused morphological changes and increased cell surface area in HEK293 cells expressing 5-HT6Rs. Treatment with 5-HT specifically increased RhoA-GTP activity without affecting other Rho family proteins, such as Rac1 and Cdc42. Furthermore, live-cell imaging in hippocampal neurons revealed that activation of 5-HT6Rs using a selective agonist, ST1936, increased the density and size of dendritic protrusions along with the activation of RhoA-GTP activity and that both effects were blocked by pretreatment with a selective 5-HT6R antagonist, SB258585. Taken together, our results show that 5-HT6R plays an important role in the regulation of cell morphology via a RhoA-dependent pathway in mammalian cell lines and primary neurons.

  • ArticleJuly 31, 2017

    10 137 2360

    Modulation of Mitochondrial Membrane Potential and ROS Generation by Nicotinamide in a Manner Independent of SIRT1 and Mitophagy

    Seon Beom Song, So-Young Jang, Hyun Tae Kang, Bie Wei, Un-woo Jeoun, Gye Soon Yoon, and Eun Seong Hwang

    Mol. Cells 2017; 40(7): 503-514 https://doi.org/10.14348/molcells.2017.0081
    Abstract

    Abstract : Nicotinamide (NAM) plays essential roles in physiology through facilitating NAD+ redox homeostasis. Importantly, at high doses, it protects cells under oxidative stresses, and has shown therapeutic effectiveness in a variety of disease conditions. In our previous studies, NAM lowered reactive oxygen species (ROS) levels and extended cellular life span in primary human cells. In the treated cells, levels of NAD+/NADH and SIRT1 activity increased, while mitochondrial content decreased through autophagy activation. The remaining mitochondria were marked with low superoxide levels and high membrane potentials (Δψm); we posited that the treatment of NAM induced an activation of mitophagy that is selective for depolarized mitochondria, which produce high levels of ROS. However, evidence for the selective mitophagy that is mediated by SIRT1 has never been provided. This study sought to explain the mechanisms by which NAM lowers ROS levels and increases Δψm. Our results showed that NAM and SIRT1 activation exert quite different effects on mitochondrial physiology. Furthermore, the changes in ROS and Δψm were not found to be mediated through autophagy or SIRT activation. Rather, NAM suppressed superoxide generation via a direct reduction of electron transport, and increased Δψm via suppression of mitochondrial permeability transition pore formation. Our results dissected the effects of cellular NAD+ redox modulation, and emphasized the importance of the NAD+/NADH ratio in the mitochondria as well as the cytosol in maintaining mitochondrial quality.

  • ArticleJuly 31, 2017

    4 92 1086

    CD133 Regulates IL-1β Signaling and Neutrophil Recruitment in Glioblastoma

    Seon Yong Lee, Jun-Kyum Kim, Hee-Young Jeon, Seok Won Ham, and Hyunggee Kim

    Mol. Cells 2017; 40(7): 515-522 https://doi.org/10.14348/molcells.2017.0089
    Abstract

    Abstract : CD133, a pentaspan transmembrane glycoprotein, is generally used as a cancer stem cell marker in various human malignancies, but its biological function in cancer cells, especially in glioma cells, is largely unknown. Here, we demonstrated that forced expression of CD133 increases the expression of IL-1β and its downstream chemokines, namely, CCL3, CXCL3 and CXCL5, in U87MG glioma cells. Although there were no apparent changes in cell growth and sphere formation in vitro and tumor growth in vivo, in vitro trans-well studies and in vivo tumor xenograft assays showed that neutrophil recruitment was markedly increased by the ectopic expression of CD133. In addition, the clinical relevance between CD133 expression and IL-1β gene signature was established in patients with malignant gliomas. Thus, these results imply that glioma cells expressing CD133 are capable of modulating tumor microenvironment through the IL-1β signaling pathway.

Mol. Cells
Dec 31, 2021 Vol.44 No.12
COVER PICTURE
Structure of the fly peripheral neurons in the fly head. Flies have basic sensory organs including eyes for vision, antennae and maxillary palps for olfaction, and proboscis (magenta) for gustation which can be labelled with monoclonal antibody 22C10. The figure is a 3D reconstructed image with 30 slices of confocal sections with 3 μm interval. It shows that the proboscis is required for sensing attractive carboxylic acids such as glycolic acid, citric acid, and lactic acid (Shrestha and Lee, pp. 900-910).

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