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Molecular and Cellular Biology

Wonkyoung Cho, Xiongjie Jin, Junfeng Pang, Yan Wang, Nahid F Mivechi, Demetrius Moskophidis
Delineating the mechanisms that drive hepatic injury and hepatocellular carcinoma (HCC) progression is critical for development of novel treatments for recurrent and advanced HCC, but also diagnostic and preventive strategies. Heat shock protein 70 (HSP70) acts in concert with several co-chaperones and nucleotide exchange factors and plays an essential role in protein quality control that increases survival by protecting cells against environmental stressors. Specifically, HSP70-mediated response has been implicated in the pathogenesis of cancer, but the specific mechanisms by which HSP70 may support malignant cell transformation remains to be fully elucidated...
February 11, 2019: Molecular and Cellular Biology
Rwik Sen, Priyanka Barman, Amala Kaja, Jannatul Ferdoush, Shweta Lahudkar, Arpan Roy, Sukesh R Bhaumik
Cap-binding complex (CBC) associates co-transcriptionally with the cap-structure at the 5'-end of nascent mRNA to protect it from exonucleolytic degradation. Here, we show that CBC promotes the targeting of mRNA export adaptor, Yra1 (that forms transcription-export or TREX complex with THO and Sub2), to the active genes to enhance mRNA export in Saccharomyces cerevisiae Likewise, recruitment of Npl3 (a heteronuclear ribonuclear protein involved in mRNA export via formation of export-competent ribonuclear protein complex or RNP) to the active genes is facilitated by CBC...
February 11, 2019: Molecular and Cellular Biology
Omar Hamdani, Namrita Dhillon, Tsung-Han S Hsieh, Takahiro Fujita, Josefina Ocampo, Jacob G Kirkland, Josh Lawrimore, Tetsuya J Kobayashi, Brandon Friedman, Derek Fulton, Kenneth Y Wu, Răzvan V Chereji, Masaya Oki, Kerry Bloom, David J Clark, Oliver J Rando, Rohinton T Kamakaka
The genome is packaged and organized in an ordered, non-random manner and specific chromatin segments contact nuclear substructures to mediate this organization. Transfer RNA genes (tDNAs) are binding sites for transcription factors and architectural proteins and are thought to play an important role in the organization of the genome. In this study, we investigate the role of tDNAs in genomic organization and chromosome function by editing a chromosome so that it lacks any tDNAs. Surprisingly our analyses of this tDNA-less chromosome show that loss of tDNAs does not grossly affect chromatin architecture or chromosome tethering and mobility...
February 4, 2019: Molecular and Cellular Biology
William N Addison, Katherine C Hall, Shoichiro Kokabu, Takuma Matsubara, Martin M Fu, Francesca Gori, Roland Baron
Satellite cells (SC) are skeletal muscle stem cells that proliferate in response to injury and provide myogenic precursors for growth and repair. Zfp423 is a transcriptional cofactor expressed in multiple immature cell populations, such as neuronal precursors, mesenchymal stem cells and preadipocytes, where it regulates lineage allocation, proliferation and differentiation. Here, we show that Zfp423 regulates myogenic progression during muscle regeneration. Zfp423 is undetectable in quiescent SCs but becomes expressed during SC activation...
January 28, 2019: Molecular and Cellular Biology
Nicholas W Eyrich, Chad R Potts, M Hope Robinson, Victor Maximov, Anna M Kenney
Cerebellar development is a highly regulated process involving numerous factors acting with high specificity, both temporally and by location. Part of this process involves extensive proliferation of cerebellar granule neuron precursors (CGNPs) induced by Sonic Hedgehog (SHH) signaling, but downstream effectors of mitogenic signaling are still being elucidated. Using primary CGNP cultures, a well-established model for SHH-driven proliferation, we show that SHH-treated CGNPs feature high levels of Hypoxia-Inducible Factor-1-Alpha (HIF1α), which is known to promote glycolysis, stemness, and angiogenesis...
January 28, 2019: Molecular and Cellular Biology
Clare C So, Shaliny Ramachandran, Alberto Martin
Histone post-translational modifications play fundamental roles in the regulation of double-stranded DNA break (DSB) repair. RNF20/RNF40-mediated monoubiquitination of histone H2B on lysine 120 (H2Bub) has been suggested as a potential mediator of DSB repair, although the nature and function of this post-translational modification remain enigmatic. In this report, we demonstrate that RNF20 and RNF40 are required for DSB repair leading to homologous recombination (HR) and class switch recombination, a process driven by non-homologous end-joining (NHEJ), in mouse B cells...
January 28, 2019: Molecular and Cellular Biology
Carmen Salvador-Palomeque, Francisco J Sanchez-Luque, Patrick R J Fortuna, Adam D Ewing, Ernst J Wolvetang, Sandra R Richardson, Geoffrey J Faulkner
The retrotransposon LINE-1 (L1) is a significant source of endogenous mutagenesis in humans. In each individual genome, a handful of retrotransposition-competent L1s (RC-L1s) can generate new heritable L1 insertions in the early embryo, primordial germline, and in germ cells. L1 retrotransposition can also occur in the neuronal lineage and cause somatic mosaicism. Although DNA methylation mediates L1 promoter repression, the temporal pattern of methylation applied to individual RC-L1s during neurogenesis is unclear...
January 28, 2019: Molecular and Cellular Biology
Laura Regué, Fei Ji, Daniel Flicker, Dana Kramer, William Pierce, Teekhon Davidoff, Jeffrey J Widrick, Nicholas Houstis, Liliana Minichiello, Ning Dai, Joseph Avruch
The IGF2 mRNA binding protein2/IMP2 was selectively deleted from adult mouse muscle; two phenotypes were observed: decreased accrual of skeletal muscle mass after weaning and reduced wheel running activity but normal forced treadmill performance. Reduced wheel running occurs when fed a high fat diet but is normalized consuming standard chow. The two phenotypes are due to altered abundance of different IMP2 client mRNAs. The reduced fiber size of IMP2 deficient muscle is attributable, in part, to diminished autocrine Igf2 production; basal tyrosine phosphorylation of the Insulin and IGF1 receptors is diminished and Akt1 activation is selectively reduced...
January 28, 2019: Molecular and Cellular Biology
Kei Saito, Tohru Fujiwara, Shunsuke Hatta, Masanobu Morita, Koya Ono, Chie Suzuki, Noriko Fukuhara, Yasushi Onishi, Yukio Nakamura, Shin Kawamata, Ritsuko Shimizu, Masayuki Yamamoto, Hideo Harigae
Ring sideroblasts are a hallmark of sideroblastic anemia, though little is known about their characteristics. Here, we first generated mutant mice by disrupting the GATA-1 binding motif at the intron 1 enhancer of the ALAS2 gene, a gene responsible for X-linked sideroblastic anemia (XLSA). Although heterozygous female mice showed an anemic phenotype, ring sideroblasts were not observed in their bone marrow. Next, we established human induced pluripotent stem cell-derived proerythroblast (HiDEP) clones harboring the same ALAS2 gene mutation...
January 22, 2019: Molecular and Cellular Biology
Anuj, Lakshmi Arivazhagan, Ganesh Venkatraman, Suresh K Rayala
Breast cancer is the recurrent type of cancer amidst women worldwide. Despite a remarkable progress in the prevention, detection and treatment of breast cancer, it still remains as a major chronic problem worldwide and poses significant challenges like metastasis to distant organs - demanding the need for novel biomarkers and therapeutic targets. Focal adhesion kinase (FAK) - a member of the protein tyrosine kinase, has been shown to be expressed in high levels in breast tumors. Of late, FAK has emerged as an impending curative target in breast carcinoma with few of the small molecular inhibitors reaching the clinical trial stage...
January 22, 2019: Molecular and Cellular Biology
Clément Immarigeon, Sandra Bernat-Fabre, Benoit Augé, Christian Faucher, Vanessa Gobert, Marc Haenlin, Lucas Waltzer, Adeline Payet, David L Cribbs, Henri-Marc G Bourbon, Muriel Boube
DNA-bound transcription factors (TFs) governing developmental gene regulation have been proposed to recruit Polymerase II machinery at gene promoters through specific interactions with dedicated subunits of the evolutionarily-conserved Mediator complex (MED). However, whether such MED subunit specific functions and partnerships have been conserved during evolution has been poorly investigated. To address this issue, we generated the first Drosophila loss-of-function mutants for Med1, known as a specific cofactor for GATA TFs and hormone nuclear receptors in mammals...
January 22, 2019: Molecular and Cellular Biology
Mathilde Soulez, Marc K Saba-El-Leil, Benjamin Turgeon, Simon Mathien, Philippe Coulombe, Sonia Klinger, Justine Rousseau, Kim Lévesque, Sylvain Meloche
The physiological functions of the atypical MAP kinase ERK3 remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus ( Mapk6lacZ ) showed that inactivation of ERK3 in Mapk6lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturation, and neuromuscular anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel mouse models expressing a catalytically-inactive ( Mapk6KD ) or conditional ( Mapk6Δ ) allele of ERK3...
January 14, 2019: Molecular and Cellular Biology
N Ronkina, K Schuster-Gossler, F Hansmann, H Kunze-Schumacher, I Sandrock, T Yakovleva, J Lafera, W Baumgärtner, A Krueger, I Prinz, A Gossler, A Kotlyarov, M Gaestel
MAPK6/ERK3 is an atypical member of the MAPKs. An essential role has been suggested by the perinatal lethal phenotype of ERK3 knockout mice carrying a lacZ insertion in exon 2 due to pulmonary disfunction and by defects in function, activation and positive selection of T cells. To study the role of ERK3 in vivo , we generated mice carrying a conditional Erk3 allele with exon3 flanked by LoxP sites. Loss of ERK3 protein was validated after deletion of Erk3 in the female germ line using zona pellucida 3 (Zp3)- cre and a clear reduction of the protein kinase MK5 is detected, providing first evidence for the existence of the ERK3/MK5 signaling complex in vivo In contrast to the previously reported Erk3 knockout phenotype, these mice are viable and fertile, do not display pulmonary hypoplasia, acute respiratory failure, abnormal T cell development, reduction of thymocyte numbers or altered T cells selection...
January 14, 2019: Molecular and Cellular Biology
Shabir Zargar, Vivek Tomar, Vidyarani Shyamsundar, Ramshankar Vijayalakshmi, Kumaravel Somasundaram, Devarajan Karunagaran
miR-155 is an oncomir, generated as a non-coding RNA from BIC gene whose promoter activity is mainly controlled via AP-1 and NF-κB transcription factors. We found that the expression levels of miR-155 and Pdcd4 exhibit inverse relationship in tongue cancer cells (SAS and AWL) and tumor tissues compared to normal FBM cells and normal tongue tissues, respectively. Insilco and In-vitro studies with 3'UTR of Pdcd4 via luciferase reporter assays, qPCR and western blots show that miR-155 directly targets Pdcd4 mRNA and blocks its expression...
January 7, 2019: Molecular and Cellular Biology
Neah Likhite, Vikas Yadav, Eric J Milliman, Danesh H Sopariwala, Sabina Lorca, Nithya P Narayana, Megha Sheth, Erin L Reineke, Vincent Giguère, Vihang Narkar
Estrogen-related receptors (ERRs) have emerged as major metabolic regulators in various tissues. However, their expression and function in the vasculature remains unknown. Here we report the transcriptional program and cellular function of ERRα in endothelial cells (ECs), a cell type with a multi-faceted role in vasculature. Of the three ERR subtypes ECs exclusively express ERRα. Gene expression profiling of ECs lacking ERRα revealed that ERRα predominantly acts as a transcriptional repressor, targeting genes linked with angiogenesis, cell migration and cell adhesion...
January 2, 2019: Molecular and Cellular Biology
Lise-Marie Donnio, Anna Lagarou, Gabrielle Sueur, Pierre-Olivier Mari, Giuseppina Giglia-Mari
DNA lesions block cellular processes such as transcription, inducing apoptosis, tissue failures and premature ageing. To counteract the deleterious effects of DNA damage, cells are equipped with various DNA repair pathways. Transcription Coupled Repair specifically removes helix-distorting DNA adducts in a coordinated multi-step process. This process has been extensively studied, however once the repair reaction is accomplished, little is known about how transcription restarts. In this study, we show that, after UV irradiation, the CDK9/CyclinT1 kinase unit is specifically released from the HEXIM1 complex and that this released fraction is degraded in the absence of CSB...
January 2, 2019: Molecular and Cellular Biology
Ana Ramón-Vázquez, Juan Vladimir de la Rosa, Carlos Tabraue, Felix Lopez, Bonifacio Nicolas Díaz-Chico, Lisardo Bosca, Peter Tontonoz, Susana Alemany, Antonio Castrillo
The liver X receptors α and β (LXRα and LXRβ) are oxysterol-activated transcription factors that coordinately regulate gene expression that is important for cholesterol and fatty acid metabolism. In addition to their roles in lipid metabolism, LXRs participate in the transcriptional regulation of macrophage activation and are considered potent regulators of inflammation. LXRs are highly similar, and despite notable exceptions, most of their reported functions are substantially overlapping. However, their individual genomic distribution and transcriptional capacities have not been characterized...
March 1, 2019: Molecular and Cellular Biology
Eunbyul Ji, Chongtae Kim, Hoin Kang, Sojin Ahn, Myeongwoo Jung, Youlim Hong, Hyosun Tak, Sukchan Lee, WooK Kim, Eun Kyung Lee
Autophagy is a lysosomal self-degradation process of cellular components by forming autophagosomes. Autophagosome formation is an essential process in autophagy, and is fine-tuned by various autophagy-related gene (ATG) molecules including ATG5, ATG12, and ATG16. Although several reports have shown that numerous factors affect multiple levels of gene regulation to orchestrate cellular autophagy, the detailed mechanism of autophagosome formation still needs further investigation. In this study, we demonstrate that RNA binding protein HuR performs an essential function in autophagosome formation...
January 2, 2019: Molecular and Cellular Biology
Shilpi Minocha, Dominic Villeneuve, Viviane Praz, Catherine Moret, Maykel Lopes, Danièle Pinatel, Leonor Rib, Nicolas Guex, Winship Herr
Host-cell factor 1 (HCF-1), encoded by the ubiquitously expressed X-linked gene Hcfc1 , is an epigenetic co-regulator important for mouse development and cell proliferation, including during liver regeneration. We used a hepatocyte-specific inducible Hcfc1 knock-out allele (called Hcfc1 hepKO ), to induce HCF-1 loss in hepatocytes of hemizygous Hcfc1 hepKO/Y males by four days. In heterozygous Hcfc1 hepKO/+ females, owing to random X-chromosome inactivation, upon Hcfc1 hepKO allele induction, a 50/50 mix of HCF-1 positive and negative hepatocyte clusters is engineered...
December 17, 2018: Molecular and Cellular Biology
Arshiya Banu, Karen J Liu, Alistair J Lax, Agamemnon E Grigoriadis
Heterotrimeric G-proteins are signal transduction proteins involved in regulating numerous signaling events. In particular, previous studies have demonstrated a role for G-proteins in regulating β-catenin signaling. However, the link between G-proteins and β-catenin signaling is controversial and appears to depend on G-protein specificity. We describe a detailed analysis of a link between specific G-alpha subunits and β-catenin using G-alpha subunit genetic knockout and knockdown approaches. The Pasteurella multocida toxin was utilized as a unique tool to activate G-proteins, with LiCl treatment serving as a β-catenin signaling agonist...
December 17, 2018: Molecular and Cellular Biology
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