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Vellingiri Balachandar, Venkatesan Dhivya, Mohan Gomathi, Subramaniam Mohanadevi, Balasubramanian Venkatesh, Bharathi Geetha
Human induced pluripotent stem cells (hiPSCs) are pluripotent stem cells generated from somatic cells by the introduction of a combination of pluripotency-associated genes such as OCT4, SOX2, along with either KLF4 and c-MYC or NANOG and LIN28 via retroviral or lentiviral vectors. Most importantly, hiPSCs are similar to human embryonic stem cells (hESCs) functionally as they are pluripotent and can potentially differentiate into any desired cell type when provided with the appropriate cues, but do not have the ethical issues surrounding hESCs...
2016: Stem Cell Investigation
Nelly Rahkonen, Aki Stubb, Maia Malonzo, Sanna Edelman, Maheswara Reddy Emani, Elisa Närvä, Harri Lähdesmäki, Hannele Ruohola-Baker, Riitta Lahesmaa, Riikka Lund
MicroRNAs (miRNA) are central regulators of diverse biological processes and are important in the regulation of stem cell self-renewal. One of the widely studied miRNA-protein regulators is the Lin28-Let-7 pair. In this study, we demonstrate that contrary to the well-established models of mouse ES cells (mESC) and transformed human cancer cells, the pluripotent state of human ES cells (hESC) involves expression of mature Let-7 family miRNAs with concurrent expression of all LIN28 proteins. We show that mature Let-7 miRNAs are regulated during hESC differentiation and have opposite expression profile with LIN28B...
September 24, 2016: Stem Cell Research
S Manier, J T Powers, A Sacco, S V Glavey, D Huynh, M R Reagan, K Z Salem, M Moschetta, J Shi, Y Mishima, C Roche-Lestienne, X Leleu, A M Roccaro, G Q Daley, I M Ghobrial
MYC is a major oncogenic driver of Multiple Myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM...
October 24, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Helen L Lightfoot, Eric A Miska, Shankar Balasubramanian
The protein Lin28 and microRNA let-7 play critical roles in mammalian development and human disease. Lin28 inhibits let-7 biogenesis through direct interaction with let-7 precursors (pre-let-7). Accumulating evidence in vitro and in vivo suggests this interaction plays a dominant role in embryonic stem cell self-renewal and tumorigenesis. Thus the Lin28-let-7 interaction might be an attractive drug target, if not for the well-known difficulties in targeting protein-RNA interactions with drugs. The identification and development of suitable probe molecules to further elucidate therapeutic potential, as well as mechanistic details of this pathway will be valuable...
October 12, 2016: Organic & Biomolecular Chemistry
Kai Yao, Suo Qiu, Lin Tian, William D Snider, John G Flannery, David V Schaffer, Bo Chen
In cold-blooded vertebrates such as zebrafish, Müller glial cells (MGs) readily proliferate to replenish lost retinal neurons. In mammals, however, MGs lack regenerative capability as they do not spontaneously re-enter the cell cycle unless the retina is injured. Here, we show that gene transfer of β-catenin in adult mouse retinas activates Wnt signaling and MG proliferation without retinal injury. Upstream of Wnt, deletion of GSK3β stabilizes β-catenin and activates MG proliferation. Downstream of Wnt, β-catenin binds to the Lin28 promoter and activates transcription...
September 27, 2016: Cell Reports
Donghyun Lim, Wan Gi Byun, Ja Young Koo, Hankum Park, Seung Bum Park
MicroRNAs (miRNAs) regulate gene expression by targeting protein-coding transcripts that are involved in various cellular processes. Thus, miRNA biogenesis has been recognized as a novel therapeutic target. Especially, the let-7 miRNA family is well-known for its tumor suppressor functions and is downregulated in many cancer cells. Lin28 protein binds to let-7 miRNA precursors to inhibit their maturation. Herein, we developed a FRET-based, high-throughput screening system to identify small-molecule inhibitors of the Lin28-let-7 interaction...
October 7, 2016: Journal of the American Chemical Society
Tomokazu Fukuda, Tetsuya Tani, Seiki Haraguchi, Kenichiro Donai, Nobuyoshi Nakajima, Hirohide Uenishi, Takahiro Eitsuka, Makoto Miyagawa, Sanghoun Song, Manabu Onuma, Yumi Hoshino, Eimei Sato, Arata Honda
In this study, we created porcine-induced pluripotent stem (iPS) cells with the expression of six reprogramming factors (Oct3/4, Klf4, Sox2, c-Myc, Lin28, and Nanog). The resulting cells showed growth dependent on LIF (leukemia inhibitory factor) and expression of multiple stem cell markers. Furthermore, the iPS cells caused teratoma formation with three layers of differentiation and had both active X chromosomes (XaXa). Our iPS cells satisfied the both of important characteristics of stem cells: teratoma formation and activation of both X chromosomes...
September 8, 2016: Journal of Cellular Biochemistry
Thomas G Papathomas, Eleonora Duregon, Esther Korpershoek, David F Restuccia, Ronald van Marion, Rocco Cappellesso, Nathalie Sturm, Giulio Rossi, Antonella Coli, Nicola Zucchini, Hans Stoop, Wolter Oosterhuis, Laura Ventura, Marco Volante, Ambrogio Fassina, Winand N M Dinjens, Mauro Papotti, Ronald R de Krijger
Adrenocortical carcinomas (ACCs) with sarcomatous areas represent an extremely rare type of highly aggressive malignancy of unknown molecular pathogenesis. The current study was planned to gain insight into its molecular genetics using a targeted next-generation sequencing approach and to explore the status of epithelial-mesenchymal transition (EMT)-associated markers (E-/P-/N-Cadherins, MMP-2/-9 and Caveolin-1), downstream transcriptional regulators of EMT-related signaling pathways (ZEB-1/-2, Slug), stem cell factors (Oct3/4, LIN28, SOX2, SO17, NANOG, CD133, nestin) and markers of adrenocortical origin/ tumorigenesis (SF-1, β-catenin, p53) in phenotypically diverse tumor components of six cases...
August 30, 2016: Human Pathology
Daniel T Peters, Herman K H Fung, Vladimir M Levdikov, Tobias Irmscher, Fiona C Warrander, Sandra J Greive, Oleg Kovalevskiy, Harry V Isaacs, Mark Coles, Alfred A Antson
Lin28A is a post-transcriptional regulator of gene expression that interacts with and negatively regulates the biogenesis of let-7 family miRNAs. Recent data suggested that Lin28A also binds the putative tumor suppressor miR-363, a member of the 106~363 cluster of miRNAs. Affinity for this miRNA and the stoichiometry of the protein-RNA complex are unknown. Characterization of human Lin28's interaction with RNA has been complicated by difficulties in producing stable RNA-free protein. We have engineered a maltose binding protein fusion with Lin28, which binds let-7 miRNA with a Kd of 54...
September 13, 2016: Biochemistry
Akimasa Seno, Tomonari Kasai, Masashi Ikeda, Arun Vaidyanath, Junko Masuda, Akifumi Mizutani, Hiroshi Murakami, Tetsuya Ishikawa, Masaharu Seno
We performed gene expression microarray analysis coupled with spherical self-organizing map (sSOM) for artificially developed cancer stem cells (CSCs). The CSCs were developed from human induced pluripotent stem cells (hiPSCs) with the conditioned media of cancer cell lines, whereas the CSCs were induced from primary cell culture of human cancer tissues with defined factors (OCT3/4, SOX2, and KLF4). These cells commonly expressed human embryonic stem cell (hESC)/hiPSC-specific genes (POU5F1, SOX2, NANOG, LIN28, and SALL4) at a level equivalent to those of control hiPSC 201B7...
2016: Cancer Informatics
Martina Roos, Ugo Pradère, Richard P Ngondo, Alok Behera, Sara Allegrini, Gianluca Civenni, Julian A Zagalak, Jean-Rémy Marchand, Mirjam Menzi, Harry Towbin, Jörg Scheuermann, Dario Neri, Amedeo Caflisch, Carlo V Catapano, Constance Ciaudo, Jonathan Hall
New discoveries in RNA biology underscore a need for chemical tools to clarify their roles in pathophysiological mechanisms. In certain cancers, synthesis of the let-7 microRNA tumor suppressor is blocked by an RNA binding protein (RBP) Lin28, which docks onto a conserved sequence in let-7 precursor RNA molecules and prevents their maturation. Thus, the Lin28/let-7 interaction might be an attractive drug target, if not for the well-known difficulty in targeting RNA-protein interactions with drugs. Here, we describe a protein/RNA FRET assay using a GFP-Lin28 donor and a black-hole quencher (BHQ)-labeled let-7 acceptor, a fluorescent protein/quencher combination which is rarely used in screening despite favorable spectral properties...
October 21, 2016: ACS Chemical Biology
Koji Harada, Tarannum Ferdous, Dan Cui, Yasuhiro Kuramitsu, Takuya Matsumoto, Eiji Ikeda, Hideyuki Okano, Yoshiya Ueyama
BACKGROUND: The cancer stem cells (CSCs), a small subpopulation of cells in tumor are responsible for the tumor initiation, growth, recurrence and metastasis of cancer, as well as resistance of cancers to drugs or radiotherapy. CSCs are an important target for the development of novel strategies in cancer treatment. However, CSCs-targeted new anti-cancer drug discovery is currently hindered by the lack of easy and reliable methods for isolating, collecting and maintaining sufficient number of CSCs...
2016: BMC Cancer
Daniel Nettersheim, Isabell Arndt, Rakesh Sharma, Stefanie Riesenberg, Sina Jostes, Simon Schneider, Michael Hölzel, Glen Kristiansen, Hubert Schorle
BACKGROUND: Cancer/testis-antigens (CTAs) are specifically expressed in human malignancies and testis tissue, but their molecular functions are poorly understood. CTAs serve as regulators of gene expression, cell cycle and spermatogenesis, as well as targets for immune-based therapies. The CTA PRAME is expressed in various cancers, antagonises retinoic acid signalling and is regulated by DNA methylation and histone acetylation. METHODS: We analysed the molecular function of the CTA PRAME in primordial germ cells (PGC) and testicular germ cell cancers (GCC)...
August 9, 2016: British Journal of Cancer
R Grant Rowe, Leo D Wang, Silvia Coma, Areum Han, Ronald Mathieu, Daniel S Pearson, Samantha Ross, Patricia Sousa, Phi T Nguyen, Antony Rodriguez, Amy J Wagers, George Q Daley
For appropriate development, tissue and organ system morphogenesis and maturation must occur in synchrony with the overall developmental requirements of the host. Mistiming of such developmental events often results in disease. The hematopoietic system matures from the fetal state, characterized by robust erythrocytic output that supports prenatal growth in the hypoxic intrauterine environment, to the postnatal state wherein granulocytes predominate to provide innate immunity. Regulation of the developmental timing of these myeloerythroid states is not well understood...
July 25, 2016: Journal of Experimental Medicine
Julie Mathieu, Hannele Ruohola-Baker
Cellular metabolism is a key regulator of cell fate, including fate in pluripotent stem cells. Now in Cell Stem Cell, Zhang et al. (2016) show that Lin28 controls the metabolic transition from naive to primed pluripotency by directly repressing oxidative metabolism genes and metabolic intermediates involved in epigenetic regulation independently of let-7.
July 7, 2016: Cell Stem Cell
Shaoguang Feng, Songsong Huang, Yulong Tong, Zhongliang Chen, Delei Shen, Dazhou Wu, Xin-He Lai, Xiaoming Chen
BACKGROUND: RNA-binding protein LIN28 is involved in maintaining the pluripotency of embryonic stem cells. It has been detected in different types of testicular and ovarian germ cell tumors (GCTs), but its status in pediatric YSTs (yolk sac tumors) is still unknown. The aim of this study was to determine the immunohistochemical profile of LIN28 in pediatric YSTs. METHODS AND RESULTS: Immunohistochemistry detection of LIN28 was performed in 22 cases of pediatric YSTs and 10 mature teratomas...
August 2016: Pediatric Surgery International
Yinshan Bai, Meiying Feng, Shanshan Liu, Hengxi Wei, Li Li, Xianwei Zhang, Chao Shen, Shouquan Zhang, Ningfang Ma
Mouse spermatogonial stem cells (mSSCs) may be reprogrammed to become pluripotent stem cells under in vitro culture conditions, due to epigenetic modifications, which are closely associated with the expression of transcription factors and epigenetic factors. Thus, this study was conducted to compare the gene expression of transcription factors and epigenetic factors in mSSCs and mouse embryonic stem cells (mESCs). Firstly, the freshly isolated mSSCs [mSSCs (f)] were enriched by magnetic-activated cell sorting with Thy1...
August 2016: International Journal of Molecular Medicine
Xuan Li, Yan-Kui Wang, Zhi-Qiang Song, Zhi-Qiang Du, Cai-Xia Yang
Meiotic maturation of mammalian oocytes is a precisely orchestrated and complex process. Dimethyl sulfoxide (DMSO), a widely used solvent, drug, and cryoprotectant, is capable of disturbing asymmetric cytokinesis of oocyte meiosis in mice. However, in pigs, DMSO's effect on oocyte meiosis still remains unknown. We aimed to evaluate if DMSO treatment will affect porcine oocyte meiosis and the underlying molecular changes as well. Interestingly, we did not observe the formation of the large first polar body and symmetric division for porcine oocytes treated with DMSO, contrary to findings reported in mice...
2016: PloS One
Susanne K Hansen, Helena Borland, Lis F Hasholt, Zeynep Tümer, Jørgen E Nielsen, Mikkel A Rasmussen, Troels T Nielsen, Tina C Stummann, Karina Fog, Poul Hyttel
Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by an expansion of the CAG-repeat in ATXN3. In this study, induced pluripotent stem cells (iPSCs) were generated from SCA3 patient dermal fibroblasts by electroporation with episomal plasmids encoding L-MYC, LIN28, SOX2, KLF4, OCT4 and short hairpin RNA targeting P53. The resulting iPSCs had normal karyotype, were free of integrated episomal plasmids, expressed pluripotency markers, could differentiate into the three germ layers in vitro and retained the disease-causing ATXN3 mutation...
May 2016: Stem Cell Research
Susanne K Hansen, Helena Borland, Lis F Hasholt, Zeynep Tümer, Jørgen E Nielsen, Mikkel A Rasmussen, Troels T Nielsen, Tina C Stummann, Karina Fog, Poul Hyttel
Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by a CAG-repeat expanding mutation in ATXN3. We generated induced pluripotent stem cells (iPSCs) from a SCA3 patient by electroporation of dermal fibroblasts with episomal plasmids encoding L-MYC, LIN28, SOX2, KLF4, OCT4 and short hairpin RNA targeting P53. The resulting iPSCs had normal karyotype, were free of genomically integrated episomal plasmids, expressed pluripotency markers, could differentiate into the three germ layers in vitro and retained the disease-causing ATXN3 mutation...
May 2016: Stem Cell Research
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