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  • MinireviewFebruary 28, 2019

    0 36 1138

    Unraveling the Paradoxical Action of Androgens on Muscle Stem Cells

    Ji-Yun Seo, Ji-Hoon Kim, and Young-Yun Kong

    Mol. Cells 2019; 42(2): 97-103 https://doi.org/10.14348/molcells.2019.0004
    Abstract

    Abstract : Androgens act in almost all tissues throughout the lifetime and have important roles in skeletal muscles. The levels of androgens increase during puberty and remain sustained at high levels in adulthood. Because androgens have an anabolic effect on skeletal muscles and muscle stem cells, these increased levels of androgens after puberty should lead to spontaneous muscle hypertrophy and hyperplasia in adulthood. However, the maintenance of muscle volume, myonuclei number per myofiber, and quiescent state of satellite cells in adulthood despite the high levels of androgens produces paradoxical outcomes. Our recent study revealed that the physiological increase of androgens at puberty initiates the transition of muscle stem cells from proliferation to quiescence by the androgen-Mindbomb1-Notch signaling axis. This newly discovered androgen action on skeletal muscles underscores the physiological importance of androgens on muscle homeostasis throughout life. This review will provide an overview of the new androgen action on skeletal muscles and discuss the paradoxical effects of androgens suggested in previous studies.

  • MinireviewFebruary 28, 2019

    0 83 2399

    Lineage Tracing: Computational Reconstruction Goes Beyond the Limit of Imaging

    Szu-Hsien (Sam) Wu, Ji-Hyun Lee, and Bon-Kyoung Koo

    Mol. Cells 2019; 42(2): 104-112 https://doi.org/10.14348/molcells.2019.0006
    Abstract

    Abstract : Tracking the fate of individual cells and their progeny through lineage tracing has been widely used to investigate various biological processes including embryonic development, homeostatic tissue turnover, and stem cell function in regeneration and disease. Conventional lineage tracing involves the marking of cells either with dyes or nucleoside analogues or genetic marking with fluorescent and/or colorimetric protein reporters. Both are imaging-based approaches that have played a crucial role in the field of developmental biology as well as adult stem cell biology. However, imaging-based lineage tracing approaches are limited by their scalability and the lack of molecular information underlying fate transitions. Recently, computational biology approaches have been combined with diverse tracing methods to overcome these limitations and so provide high-order scalability and a wealth of molecular information. In this review, we will introduce such novel computational methods, starting from single-cell RNA sequencing-based lineage analysis to DNA barcoding or genetic scar analysis. These novel approaches are complementary to conventional imaging-based approaches and enable us to study the lineage relationships of numerous cell types during vertebrate, and in particular human, development and disease.

  • ArticleFebruary 28, 2019

    0 65 702

    Loss of Primary Cilia Results in the Development of Cancer in the Murine Thyroid Gland

    Junguee Lee, Shinae Yi, Joon Young Chang, Jung Tae Kim, Hae Joung Sul, Ki Cheol Park, Xuguang Zhu, Sheue-yann Cheng, Jukka Kero, Joon Kim, and Minho Shong

    Mol. Cells 2019; 42(2): 113-122 https://doi.org/10.14348/molcells.2018.0430
    Abstract

    Abstract : Communications at the interface between the apical membrane of follicular cells and the follicular lumen are critical for the homeostasis of thyroid gland. Primary cilia at the apical membrane of thyroid follicular cells may sense follicular luminal environment and regulate follicular homeostasis, although their role in vivo remains to be determined. Here, mice devoid of primary cilia were generated by thyroid follicular epithelial cell-specific deletion of the gene encoding intraflagellar transport protein 88 (Ift88 ). Thyroid follicular cell-specific Ift88-deficient mice showed normal folliculogenesis and hormonogenesis; however, those older than 7 weeks showed irregularly dilated and destroyed follicles in the thyroid gland. With increasing age, follicular cells with malignant properties showing the characteristic nuclear features of human thyroid carcinomas formed papillary and solid proliferative nodules from degenerated thyroid follicles. Furthermore, malignant tumor cells manifested as tumor emboli in thyroid vessels. These findings suggest that loss-of-function of Ift88/primary cilia results in malignant transformation from degenerated thyroid follicles.

  • ArticleFebruary 28, 2019

    0 33 678

    HeLa E-Box Binding Protein, HEB, Inhibits Promoter Activity of the Lysophosphatidic Acid Receptor Gene Lpar1 in Neocortical Neuroblast Cells

    Nam-Ho Kim, Ali Sadra, Hee-Young Park, Sung-Min Oh, Jerold Chun, Jeong Kyo Yoon, and Sung-Oh Huh

    Mol. Cells 2019; 42(2): 123-134 https://doi.org/10.14348/molcells.2018.0399
    Abstract

    Abstract : Lysophosphatidic acid (LPA) is an endogenous lysophospholipid with signaling properties outside of the cell and it signals through specific G protein-coupled receptors, known as LPA1?6. For one of its receptors, LPA1 (gene name Lpar1), details on the cis-acting elements for transcriptional control have not been defined. Using 5′RACE analysis, we report the identification of an alternative transcription start site of mouse Lpar1 and characterize approximately 3,500 bp of non-coding flanking sequence 5′ of mouse Lpar1 gene for promoter activity. Transient transfection of cells derived from mouse neocortical neuroblasts with constructs from the 5′ regions of mouse Lpar1 gene revealed the region between ?248 to +225 serving as the basal promoter for Lpar1. This region also lacks a TATA box. For the region between ?761 to ?248, a negative regulatory element affected the basal expression of Lpar1. This region has three E-box sequences and mutagenesis of these E-boxes, followed by transient expression, demonstrated that two of the E-boxes act as negative modulators of Lpar1. One of these E-box sequences bound the HeLa E-box binding protein (HEB), and modulation of HEB levels in the transfected cells regulated the transcription of the reporter gene. Based on our data, we propose that HEB may be required for a proper regulation of Lpar1 expression in the embryonic neocortical neuroblast cells and to affect its function in both normal brain development and disease settings.

  • ArticleFebruary 28, 2019

    0 47 699

    OCT4B Isoform Promotes Anchorage-Independent Growth of Glioblastoma Cells

    Sang-Hun Choi, Jun-Kyum Kim, Hee-Young Jeon, Kiyoung Eun, and Hyunggee Kim

    Mol. Cells 2019; 42(2): 135-142 https://doi.org/10.14348/molcells.2018.0311
    Abstract

    Abstract : OCT4, also known as POU5F1 (POU domain class 5 transcription factor 1), is a transcription factor that acts as a master regulator of pluripotency in embryonic stem cells and is one of the reprogramming factors required for generating induced pluripotent stem cells. The human OCT4 encodes three isoforms, OCT4A, OCT4B, and OCT4B1, which are generated by alternative splicing. Currently, the functions and expression patterns of OCT4B remain largely unknown in malignancies, especially in human glioblastomas. Here, we demonstrated the function of OCT4B in human glioblastomas. Among the isoform of OCT4B, OCT4B-190 (OCT4B19kDa) was highly expressed in human glioblastoma stem cells and glioblastoma cells and was mainly detected in the cytoplasm rather than the nucleus. Overexpression of OCT4B19kDa promoted colony formation of glioblastoma cells when grown in soft agar culture conditions. Clinical data analysis revealed that patients with gliomas that expressed OCT4B at high levels had a poorer prognosis than patients with gliomas that expressed OCT4B at low levels. Thus, OCT4B19kDa may play a crucial role in regulating cancer cell survival and adaption in a rigid environment.

  • ArticleFebruary 28, 2019

    0 55 624

    Role of Dehydrocorybulbine in Neuropathic Pain After Spinal Cord Injury Mediated by P2X4 Receptor

    Zhongwei Wang, Wei Mei, Qingde Wang, Rundong Guo, Peilin Liu, Yuqiang Wang, Zijuan Zhang, and Limin Wang

    Mol. Cells 2019; 42(2): 143-150 https://doi.org/10.14348/molcells.2018.0028
    Abstract

    Abstract : Chronic neuropathic pain is one of the primary causes of disability subsequent to spinal cord injury. Patients experiencing neuropathic pain after spinal cord injury suffer from poor quality of life, so complementary therapy is seriously needed. Dehydrocorybulbine is an alkaloid extracted from Corydalis yanhusuo. It effectively alleviates neuropathic pain. In the present study, we explored the effect of dehydrocorybulbine on neuropathic pain after spinal cord injury and delineated its possible mechanism. Experiments were performed in rats to evaluate the contribution of dehydrocorybulbine to P2X4 signaling in the modulation of pain-related behaviors and the levels of pronociceptive interleukins and proteins after spinal cord injury. In a rat contusion injury model, we confirmed that chronic neuropathic pain is present on day 7 after spinal cord injury and P2X4R expression is exacerbated after spinal cord injury. We also found that administration of dehydrocorybulbine by tail vein injection relieved pain behaviors in rat contusion injury models without affecting motor functions. The elevation in the levels of pronociceptive interleukins (IL-1β, IL-18, MMP-9) after spinal cord injury was mitigated by dehydrocorybulbine. Dehydrocorybulbine significantly mitigated the upregulation of P2X4 receptor and reduced ATP-evoked intracellular Ca2+ concentration. Both P2XR and dopamine receptor2 agonists antagonized dehydrocorybulbine’s antinociceptive effects. In conclusion, we propose that dehydrocorybulbine produces antinociceptive effects in spinal cord injury models by inhibiting P2X4R.

  • ArticleFebruary 28, 2019

    0 53 691
    Abstract

    Abstract : Ultraviolet (UV) radiation of the sunlight, especially UVA and UVB, is the primary environmental cause of skin damage, including topical inflammation, premature skin aging, and skin cancer. Previous reports show that activation of nuclear factor-κB (NF-κB) in human skin fibroblasts and keratinocytes after UV exposure induces the expression and release of proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), and subsequently leads to the production of matrix metalloproteases (MMPs) and growth factor basic fibroblast growth factor (bFGF). Here, we demonstrated that TNFR2-SKEE and TNFR2-SKE, oligopeptides from TNF receptor-associated factor 2 (TRAF2)-binding site of TNF receptor 2 (TNFR2), strongly inhibited the interaction of TNFR1 as well as TNFR2 with TRAF2. In particular, TNFR2-SKE suppressed UVB- or TNF-α-induced nuclear translocalization of activated NF-κB in mouse fibroblasts. It decreased the expression of bFGF, MMPs, and COX2, which were upregulated by TNF-α, and increased procollagen production, which was reduced by TNF-α. Furthermore, TNFR2-SKE inhibited the UVB-induced proliferation of keratinocytes and melanocytes in the mouse skin and the infiltration of immune cells into inflamed tissues. These results suggest that TNFR2-SKE may possess the clinical potency to alleviate UV-induced photoaging in human skin.

  • ArticleFebruary 28, 2019

    0 33 874

    TGFBI Promoter Methylation is Associated with Poor Prognosis in Lung Adenocarcinoma Patients

    Yangki Seok, Won Kee Lee, Jae Yong Park, and Dong Sun Kim

    Mol. Cells 2019; 42(2): 161-165 https://doi.org/10.14348/molcells.2018.0322
    Abstract

    Abstract : Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide and has high rates of metastasis. Transforming growth factor beta-inducible protein (TGFBI) is an extracellular matrix component involved in tumour growth and metastasis. However, the exact role of TGFBI in NSCLC remains controversial. Gene silencing via DNA methylation of the promoter region is common in lung tumorigenesis and could thus be used for the development of molecular biomarkers. We analysed the methylation status of the TGFBI promoter in 138 NSCLC specimens via methylation-specific PCR and evaluated the correlation between TGFBI methylation and patient survival. TGFBI promoter methylation was detected in 25 (18.1%) of the tumours and was demonstrated to be associated with gene silencing. We observed no statistical correlation between TGFBI methylation and clinicopathological characteristics. Univariate and multivariate analyses showed that TGFBI methylation is significantly associated with poor survival outcomes in adenocarcinoma cases (adjusted hazard ratio = 2.88, 95% confidence interval = 1.19?6.99, P = 0.019), but not in squamous cell cases. Our findings suggest that methylation in the TGFBI promoter may be associated with pathogenesis of NSCLC and can be used as a predictive marker for lung adenocarcinoma prognosis. Further large-scale studies are needed to confirm these findings.

  • ArticleFebruary 28, 2019

    0 45 450
    Abstract

    Abstract : Bacterial species in the genus Xanthomonas infect virtually all crop plants. Although many genes involved in Xanthomonas virulence have been identified through molecular and cellular studies, the elucidation of virulence-associated regulatory circuits is still far from complete. Functional gene networks have proven useful in generating hypotheses for genetic factors of biological processes in various species. Here, we present a genome-scale co-functional network of Xanthomonas oryze pv. oryzae (Xoo) genes, XooNet (www.inetbio.org/xoonet/), constructed by integrating heterogeneous types of genomics data derived from Xoo and other bacterial species. XooNet contains 106,000 functional links, which cover approximately 83% of the coding genome. XooNet is highly predictive for diverse biological processes in Xoo and can accurately reconstruct cellular pathways regulated by two-component signaling transduction systems (TCS). XooNet will be a useful in silico research platform for genetic dissection of virulence pathways in Xoo.

  • ArticleFebruary 28, 2019

    0 41 343

    The MicroRNA-551a/MEF2C Axis Regulates the Survival and Sphere Formation of Cancer Cells in Response to 5-Fluorouracil

    Hoin Kang, Chongtae Kim, Eunbyul Ji, Sojin Ahn, Myeongwoo Jung, Youlim Hong, WooK Kim, and Eun Kyung Lee

    Mol. Cells 2019; 42(2): 175-182 https://doi.org/10.14348/molcells.2018.0288
    Abstract

    Abstract : microRNAs regulate a diverse spectrum of cancer biology, including tumorigenesis, metastasis, stemness, and drug resistance. To investigate miRNA-mediated regulation of drug resistance, we characterized the resistant cell lines to 5-fluorouracil by inducing stable expression of miRNAs using lenti-miRNA library. Here, we demonstrate miR-551a as a novel factor regulating cell survival after 5-FU treatment. miR-551a-expressing cells (Hep3B-lenti-miR-551a) were resistant to 5-FU-induced cell death, and after 5-FU treatment, and showed significant increases in cell viability, cell survival, and sphere formation. It was further shown that myocyte-specific factor 2C is the direct target of miR-551a. Our results suggest that miR-551a plays a novel function in regulating 5-FU-induced cell death, and targeting miR-551a might be helpful to sensitize cells to anti-cancer drugs.

Mol. Cells
Nov 30, 2021 Vol.44 No.11
COVER PICTURE
3D quantitative images of the vesicular structure and the nucleolus using label free optical diffraction tomography (Kim et al., pp. 851-860).

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