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  • MinireviewJanuary 31, 2020

    0 677 1342

    Lung Cancer Staging and Associated Genetic and Epigenetic Events

    Dohun Kim, You-Soub Lee, Duk-Hwan Kim, and Suk-Chul Bae

    Mol. Cells 2020; 43(1): 1-9 https://doi.org/10.14348/molcells.2020.2246
    Abstract

    Abstract : The first step in treating lung cancer is to establish the stage of the disease, which in turn determines the treatment options and prognosis of the patient. Many factors are involved in lung cancer staging, but all involve anatomical information. However, new approaches, mainly those based on the molecular biology of cancer, have recently changed the paradigm for lung cancer treatment and have not yet been incorporated into staging. In a group of patients of the same stage who receive the same treatment, some may experience unexpected recurrence or metastasis, largely because current staging methods do not reflect the findings of molecular biological studies. In this review, we provide a brief summary of the latest research on lung cancer staging and the molecular events associated with carcinogenesis. We hope that this paper will serve as a bridge between clinicians and basic researchers and aid in our understanding of lung cancer.

  • MinireviewJanuary 31, 2020

    0 1055 1667

    Mitophagy and Innate Immunity in Infection

    Dong-Hyung Cho, Jin Kyung Kim, and Eun-Kyeong Jo

    Mol. Cells 2020; 43(1): 10-22 https://doi.org/10.14348/molcells.2020.2329
    Abstract

    Abstract : Mitochondria have several quality control mechanisms by which they maintain cellular homeostasis and ensure that the molecular machinery is protected from stress. Mitophagy, selective autophagy of mitochondria, promotes mitochondrial quality control by inducing clearance of damaged mitochondria via the autophagic machinery. Accumulating evidence suggests that mitophagy is modulated by various microbial components in an attempt to affect the innate immune response to infection. In addition, mitophagy plays a key role in the regulation of inflammatory signaling, and mitochondrial danger signals such as mitochondrial DNA translocated into the cytosol can lead to exaggerated inflammatory responses. In this review, we present current knowledge on the functional aspects of mitophagy and its crosstalk with innate immune signaling during infection. A deeper understanding of the role of mitophagy could facilitate the development of more effective therapeutic strategies against various infections.

  • Research ArticleJanuary 31, 2020

    0 566 708

    The Tumor Suppressor, p53, Negatively Regulates Non-Canonical NF-κB Signaling through miRNAInduced Silencing of NF-κB?Inducing Kinase

    Hanbit Jang, Seulki Park, Jaehoon Kim, Jong Hwan Kim, Seon-Young Kim, Sayeon Cho, Sung Goo Park, Byoung Chul Park, Sunhong Kim, and Jeong-Hoon Kim

    Mol. Cells 2020; 43(1): 23-33 https://doi.org/10.14348/molcells.2019.0239
    Abstract

    Abstract : NF-κB signaling through both canonical and non-canonical pathways plays a central role in immune responses and inflammation. NF-κB?inducing kinase (NIK) stabilization is a key step in activation of the non-canonical pathway and its dysregulation implicated in various hematologic malignancies. The tumor suppressor, p53, is an established cellular gatekeeper of proliferation. Abnormalities of the TP53 gene have been detected in more than half of all human cancers. While the non-canonical NF-κB and p53 pathways have been explored for several decades, no studies to date have documented potential cross-talk between these two cancer-related mechanisms. Here, we demonstrate that p53 negatively regulates NIK in an miRNA-dependent manner. Overexpression of p53 decreased the levels of NIK, leading to inhibition of the non-canonical NF-κB pathway. Conversely, its knockdown led to increased levels of NIK, IKKα phosphorylation, and p100 processing. Additionally, miR-34b induced by nutlin-3 directly targeted the coding sequences (CDS) of NIK. Treatment with anti-miR-34b-5p augmented NIK levels and subsequent non-canonical NF-κB signaling. Our collective findings support a novel cross-talk mechanism between non-canonical NF-κB and p53.

  • Research ArticleJanuary 31, 2020

    0 479 863

    Rev-erbα Negatively Regulates Osteoclast and Osteoblast Differentiation through p38 MAPK Signaling Pathway

    Kabsun Kim, Jung Ha Kim, Inyoung Kim, Semun Seong, and Nacksung Kim

    Mol. Cells 2020; 43(1): 34-47 https://doi.org/10.14348/molcells.2019.0232
    Abstract

    Abstract : The circadian clock regulates various physiological processes, including bone metabolism. The nuclear receptors Rev-erbs, comprising Rev-erbα and Rev-erbβ, play a key role as transcriptional regulators of the circadian clock. In this study, we demonstrate that Rev-erbs negatively regulate differentiation of osteoclasts and osteoblasts. The knockdown of Rev-erbα in osteoclast precursor cells enhanced receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation, as well as expression of nuclear factor of activated T cells 1 (NFATc1), osteoclast-associated receptor (OSCAR), and tartrate-resistant acid phosphatase (TRAP). The overexpression of Rev-erbα leads to attenuation of the NFATc1 expression via inhibition of recruitment of c-Fos to the NFATc1 promoter. The overexpression of Rev-erbα in osteoblast precursors attenuated the expression of osteoblast marker genes including Runx2, alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OC). Rev-erbα interfered with the recruitment of Runx2 to the promoter region of the target genes. Conversely, knockdown of Rev-erbα in the osteoblast precursors enhanced the osteoblast differentiation and function. In addition, Rev-erbα negatively regulated osteoclast and osteoblast differentiation by suppressing the p38 MAPK pathway. Furthermore, intraperitoneal administration of GSK4112, a Rev-erb agonist, protects RANKL-induced bone loss via inhibition of osteoclast differentiation in vivo. Taken together, our results demonstrate a molecular mechanism of Rev-erbs in the bone remodeling, and provide a molecular basis for a potential therapeutic target for treatment of bone disease characterized by excessive bone resorption.

  • Research ArticleJanuary 31, 2020

    0 519 967

    CrABCA2 Facilitates Triacylglycerol Accumulation in Chlamydomonas reinhardtii under Nitrogen Starvation

    Sunghoon Jang, Fantao Kong, Jihyeon Lee, Bae Young Choi, Pengfei Wang, Peng Gao, Takashi Yamano, Hideya Fukuzawa, Byung-Ho Kang, and Youngsook Lee

    Mol. Cells 2020; 43(1): 48-57 https://doi.org/10.14348/molcells.2019.0262
    Abstract

    Abstract : The microalga Chlamydomonas reinhardtii accumulates triacylglycerols (TAGs) in lipid droplets under stress conditions, such as nitrogen starvation. TAG biosynthesis occurs mainly at the endoplasmic reticulum (ER) and requires fatty acid (FA) substrates supplied from chloroplasts. How FAs are transferred from chloroplast to ER in microalgae was unknown. We previously reported that an Arabidopsis thaliana ATP-binding cassette (ABC) transporter, AtABCA9, facilitates FA transport at the ER during seed development. Here we identified a gene homologous to AtABCA9 in the C. reinhardtii genome, which we named CrABCA2. Under nitrogen deprivation conditions, CrABCA2 expression was upregulated, and the CrABCA2 protein level also increased. CrABCA2 knockdown lines accumulated less TAGs and CrABCA2 overexpression lines accumulated more TAGs than their untransformed parental lines. Transmission electron microscopy showed that CrABCA2 was localized in swollen ER. These results suggest that CrABCA2 transports substrates for TAG biosynthesis to the ER during nitrogen starvation. Our study provides a potential tool for increasing lipid production in microalgae.

  • Research ArticleJanuary 31, 2020

    0 458 603
    Abstract

    Abstract : Fat mass and obesity-associated (FTO) gene helps to regulate energy homeostasis in mammals by controlling energy expenditure. In addition, FTO functions in the regulation of obesity and adipogenic differentiation; however, a role in osteogenic differentiation is unknown. This study investigated the effects of FTO on osteogenic differentiation of C3H10T1/2 cells and the underlying mechanism. Expression of osteogenic and endoplasmic reticulum (ER) stress markers were characterized by reverse-transcriptase polymerase chain reaction and western blotting. Alkaline phosphatase (ALP) staining was performed to assess ALP activity. BMP2 treatment increased mRNA expression of osteogenic genes and FTO. Overexpression of FTO increased expression of the osteogenic genes distal-less homeobox5 (Dlx5) and runt-related transcription factor 2 (Runx2). Activation of adenosine monophosphate-activated protein kinase (AMPK) increased FTO expression, and there was a positive feedback loop between FTO and p-AMPK. p-AMPK and FTO induced mild ER stress; however, tunicamycin-induced severe ER stress suppressed FTO expression and AMPK activation. In summary, FTO induces osteogenic differentiation of C3H10T1/2 cells upon BMP2 treatment by inducing mild ER stress via a positive feedback loop with p-AMPK. FTO expression and AMPK activation induce mild ER stress. By contrast, severe ER stress inhibits osteogenic differentiation by suppressing FTO expression and AMPK activation.

  • Research ArticleJanuary 31, 2020

    0 693 854

    Mitochondrial Ca2+ Uptake Relieves Palmitate-Induced Cytosolic Ca2+ Overload in MIN6 Cells

    Luong Dai Ly, Dat Da Ly, Nhung Thi Nguyen, Ji-Hee Kim, Heesuk Yoo, Jongkyeong Chung, Myung-Shik Lee, Seung-Kuy Cha, and Kyu-Sang Park

    Mol. Cells 2020; 43(1): 66-75 https://doi.org/10.14348/molcells.2019.0223
    Abstract

    Abstract : Saturated fatty acids contribute to β-cell dysfunction in the onset of type 2 diabetes mellitus. Cellular responses to lipotoxicity include oxidative stress, endoplasmic reticulum (ER) stress, and blockage of autophagy. Palmitate induces ER Ca2+ depletion followed by notable store-operated Ca2+ entry. Subsequent elevation of cytosolic Ca2+ can activate undesirable signaling pathways culminating in cell death. Mitochondrial Ca2+ uniporter (MCU) is the major route for Ca2+ uptake into the matrix and couples metabolism with insulin secretion. However, it has been unclear whether mitochondrial Ca2+ uptake plays a protective role or contributes to lipotoxicity. Here, we observed palmitate upregulated MCU protein expression in a mouse clonal β-cell, MIN6, under normal glucose, but not high glucose medium. Palmitate elevated baseline cytosolic Ca2+ concentration ([Ca2+]i) and reduced depolarization-triggered Ca2+ influx likely due to the inactivation of voltage-gated Ca2+ channels (VGCCs). Targeted reduction of MCU expression using RNA interference abolished mitochondrial superoxide production but exacerbated palmitate-induced [Ca2+]i overload. Consequently, MCU knockdown aggravated blockage of autophagic degradation. In contrast, co-treatment with verapamil, a VGCC inhibitor, prevented palmitate-induced basal [Ca2+]i elevation and defective [Ca2+]i transients. Extracellular Ca2+ chelation as well as VGCC inhibitors effectively rescued autophagy defects and cytotoxicity. These observations suggest enhanced mitochondrial Ca2+ uptake via MCU upregulation is a mechanism by which pancreatic β-cells are able to alleviate cytosolic Ca2+ overload and its detrimental consequences.

  • Research ArticleJanuary 31, 2020

    0 402 571

    march5 Governs the Convergence and Extension Movement for Organization of the Telencephalon and Diencephalon in Zebrafish Embryos

    Jangham Jung, Issac Choi, Hyunju Ro, Tae-Lin Huh, Joonho Choe, and Myungchull Rhee

    Mol. Cells 2020; 43(1): 76-85 https://doi.org/10.14348/molcells.2019.0210
    Abstract

    Abstract : MARCH5 is a RING finger E3 ligase involved in mitochondrial integrity, cellular protein homeostasis, and the regulation of mitochondrial fusion and fission. To determine the function of MARCH5 during development, we assessed transcript expression in zebrafish embryos. We found that march5 transcripts were of maternal origin and evenly distributed at the 1-cell stage, except for the mid-blastula transition, with expression predominantly in the developing central nervous system at later stages of embryogenesis. Overexpression of march5 impaired convergent extension movement during gastrulation, resulting in reduced patterning along the dorsoventral axis and alterations in the ventral cell types. Overexpression and knockdown of march5 disrupted the organization of the developing telencephalon and diencephalon. Lastly, we found that the transcription of march5 was tightly regulated by the transcriptional regulators CHOP, C/EBPα, Staf, Znf143a, and Znf76. These results demonstrate the essential role of March5 in the development of zebrafish embryos.

  • Research ArticleJanuary 31, 2020

    0 506 780

    Whole Genome Analysis of the Red-Crowned Crane Provides Insight into Avian Longevity

    HyeJin Lee, Jungeun Kim, Jessica A. Weber, Oksung Chung, Yun Sung Cho, Sungwoong Jho, JeHoon Jun, Hak-Min Kim, Jeongheui Lim, Jae-Pil Choi, Sungwon Jeon, Asta Blazyte, Jeremy S. Edwards, Woon Kee Paek, and Jong Bhak

    Mol. Cells 2020; 43(1): 86-95 https://doi.org/10.14348/molcells.2019.0190
    Abstract

    Abstract : The red-crowned crane (Grus japonensis) is an endangered, large-bodied crane native to East Asia. It is a traditional symbol of longevity and its long lifespan has been confirmed both in captivity and in the wild. Lifespan in birds is known to be positively correlated with body size and negatively correlated with metabolic rate, though the genetic mechanisms for the red-crowned crane’s long lifespan have not previously been investigated. Using whole genome sequencing and comparative evolutionary analyses against the grey-crowned crane and other avian genomes, including the long-lived common ostrich, we identified red-crowned crane candidate genes with known associations with longevity. Among these are positively selected genes in metabolism and immunity pathways (NDUFA5, NDUFA8, NUDT12, SOD3, CTH, RPA1, PHAX, HNMT, HS2ST1, PPCDC, PSTK CD8B, GP9, IL-9R, and PTPRC). Our analyses provide genetic evidence for low metabolic rate and longevity, accompanied by possible convergent adaptation signatures among distantly related large and long-lived birds. Finally, we identified low genetic diversity in the red-crowned crane, consistent with its listing as an endangered species, and this genome should provide a useful genetic resource for future conservation studies of this rare and iconic species.

Mol. Cells
Sep 30, 2022 Vol.45 No.9
COVER PICTURE
The Target of Rapamycin Complex (TORC) is a central regulatory hub in eukaryotes, which is well conserved in diverse plant species, including tomato (Solanum lycopersicum). Inhibition of TORC genes (SlTOR, SlLST8, and SlRAPTOR) by VIGS (virus-induced gene silencing) results in early fruit ripening in tomato. The red/ orange tomatoes are early-ripened TORC-silenced fruits, while the green tomato is a control fruit. Top, left, control fruit (TRV2-myc); top, right, TRV2-SlLST8; bottom, left, TRV2-SlTOR; bottom, right, TRV2-SlRAPTOR(Choi et al., pp. 660-672).

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