Open AccessJournal Article
Notch Signaling Induces Cell Cycle Arrest in Small Cell Lung Cancer Cells
Virote Sriuranpong,Michael Borges,Rajani Ravi,Dagmar R. Arnold,Barry D. Nelkin,Stephen B. Baylin,Douglas W. Ball +6 more
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TLDR
Notch activation, in the setting of a highly proliferative hASH1-dependent NE neoplasm, can be associated with growth arrest and apparent reduction in neoplastic potential, suggesting that the previously described function of Notch proteins as proto-oncogenes is highly context-dependent.Abstract:
Among the various forms of human lung cancer, small cell lung cancer (SCLC) exhibits a characteristic neuroendocrine (NE) phenotype. Neural and NE differentiation in SCLC depend, in part, on the action of the basic-helix-loop-helix (bHLH) transcription factor human achaete-scute homologue-1 (hASH1). In nervous system development, the Notch signaling pathway is a critical negative regulator of bHLH factors, including hASH1, controlling cell fate commitment and differentiation. To characterize Notch pathway function in SCLC, we explored the consequences of constitutively active Notch signaling in cultured SCLC cells. Recombinant adenoviruses were used to overexpress active forms of Notch1, Notch2, or the Notch effector protein human hairy enhancer of split-1 (HES1) in DMS53 and NCI-H209 SCLC cells. Notch proteins, but not HES1 or control adenoviruses, caused a profound growth arrest, associated with a G 1 cell cycle block. We found up-regulation of p21 waf1/cip1 and p27 kip1 in concert with the cell cycle changes. Active Notch proteins also led to dramatic reduction in hASH1 expression, as well as marked activation of phosphorylated extracellular signal-regulated kinase (ERK)1 and ERK2, findings that have been shown to be associated with cell cycle arrest in SCLC cells. These data suggest that the previously described function of Notch proteins as proto-oncogenes is highly context-dependent. Notch activation, in the setting of a highly proliferative hASH1-dependent NE neoplasm, can be associated with growth arrest and apparent reduction in neoplastic potential.read more
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Journal ArticleDOI
Comprehensive genomic profiles of small cell lung cancer
Julie George,Jing Shan Lim,Se Jin Jang,Yupeng Cun,Luka Ozretić,Gu Kong,Frauke Leenders,Xin Lu,Lynnette Fernandez-Cuesta,Graziella Bosco,Christian Müller,Ilona Dahmen,Nadine Jahchan,Kwon-Sik Park,Dian Yang,Anthony N. Karnezis,Dedeepya Vaka,Ángela Torres,Maia Segura Wang,Jan O. Korbel,Roopika Menon,Sung-Min Chun,Deokhoon Kim,Matthew D. Wilkerson,Neil Hayes,David Engelmann,Brigitte M. Pützer,Marc Bos,Sebastian Michels,Ignacija Vlasic,Danila Seidel,Berit Pinther,Philipp Schaub,Christian Becker,Janine Altmüller,Jun Yokota,Takashi Kohno,Reika Iwakawa,Koji Tsuta,Masayuki Noguchi,Thomas Muley,Hans Hoffmann,Philipp A. Schnabel,Iver Petersen,Yuan Chen,Alex Soltermann,Verena Tischler,Chang-Min Choi,Yong-Hee Kim,Pierre P. Massion,Yong Zou,Dragana Jovanovic,Milica Kontic,Gavin M. Wright,Prudence A. Russell,Benjamin Solomon,Ina Koch,Michael Lindner,Lucia Anna Muscarella,Annamaria la Torre,John K. Field,Marko Jakopović,Jelena Knezevic,Esmeralda Castaños-Vélez,Luca Roz,Ugo Pastorino,O.T. Brustugun,Marius Lund-Iversen,Erik Thunnissen,Jens Köhler,Martin Schuler,Johan Botling,Martin Sandelin,Montserrat Sanchez-Cespedes,Helga B. Salvesen,Viktor Achter,Ulrich Lang,Magdalena Bogus,Peter M. Schneider,Thomas Zander,Sascha Ansén,Michael Hallek,Jürgen Wolf,Martin Vingron,Yasushi Yatabe,William D. Travis,Peter Nürnberg,Christian Reinhardt,Sven Perner,Lukas C. Heukamp,Reinhard Büttner,Stefan A. Haas,Elisabeth Brambilla,Martin Peifer,Julien Sage,Roman K. Thomas +95 more
TL;DR: This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
Journal ArticleDOI
The role of Notch in tumorigenesis: oncogene or tumour suppressor?
Freddy Radtke,Kenneth Raj +1 more
TL;DR: There is mounting evidence that Notch signalling is not exclusively oncogenic and can instead function as a tumour suppressor.
Journal ArticleDOI
Notch mediates TGFα-induced changes in epithelial differentiation during pancreatic tumorigenesis
Yoshiharu Miyamoto,Anirban Maitra,Bidyut Ghosh,Ulrich Zechner,Pedram Argani,Christine A. Iacobuzio-Donahue,Virote Sriuranpong,Tatsuya Iso,Ingrid M. Meszoely,Michael S. Wolfe,Ralph H. Hruban,Douglas W. Ball,Roland M. Schmid,Steven D. Leach +13 more
TL;DR: It is suggested that Notch mediates the tumor-initiating effects of TG alpha by expanding a population of undifferentiated precursor cells.
Journal ArticleDOI
NOTCH Pathway Blockade Depletes CD133‐Positive Glioblastoma Cells and Inhibits Growth of Tumor Neurospheres and Xenografts
Xing Fan,Leila Khaki,Thant S. Zhu,Mary E. Soules,Caroline E. Talsma,Naheed Gul,Cheryl M. Koh,Jiangyang Zhang,Yue Ming Li,Jarek Maciaczyk,Guido Nikkhah,Francesco DiMeco,Sara Grazia Maria Piccirillo,Angelo L. Vescovi,Charles G. Eberhart +14 more
TL;DR: It is demonstrated that NOTCH pathway blockade depletes stem‐like cells in GBMs, suggesting that GSIs may be useful as chemotherapeutic reagents to target CSCs in malignant gliomas.
Journal ArticleDOI
Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation.
Benjamin Purow,Raqeeb M. Haque,Martha Noel,Qin Su,Michael J. Burdick,Jeongwu Lee,Tilak K. Sundaresan,Sandra Pastorino,John K. Park,Irina Mikolaenko,Dragan Maric,Charles G. Eberhart,Howard A. Fine +12 more
TL;DR: These results show, for the first time, the dependence of cancer cells on a single Notch ligand; they suggest a potential Notch juxtacrine/autocrine loop in gliomas and may present novel therapeutic targets in the treatment of glioma.
References
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Journal ArticleDOI
Notch Signaling: Cell Fate Control and Signal Integration in Development
TL;DR: Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development, providing a general developmental tool to influence organ formation and morphogenesis.
Journal Article
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PatentDOI
A simplified system for generating recombinant adenoviruses
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Journal Article
Evaluation of a Soluble Tetrazolium/Formazan Assay for Cell Growth and Drug Sensitivity in Culture Using Human and Other Tumor Cell Lines
Dominic A. Scudiero,Robert H. Shoemaker,Kenneth D. Paull,Anne Monks,Siobhan Tierney,Thomas H. Nofziger,Michael J. Currens,Donna Seniff,Michael R. Boyd +8 more
TL;DR: The new XTT reagent provides for a simplified, in vitro cell growth assay with possible applicability to a variety of problems in cellular pharmacology and biology, but still shares many of the limitations and potential pitfalls of MTT or other tetrazolium-based assays.
Journal ArticleDOI
TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.
Leif W. Ellisen,Jeffrey Bird,Daniel C. West,A. Lee Soreng,Thomas C. Reynolds,Stephen D. Smith,Jeffrey Sklar +6 more
TL;DR: It is shown that the locus on chromosome 9 contains a gene highly homologous to the Drosophila gene Notch, which may be important for normal lymphocyte function and that alteration of TAN-1 may play a role in the pathogenesis of some T cell neoplasms.
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