Journal ArticleDOI
Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells.
Sanne Weijzen,Paola Rizzo,Mike Braid,Radhika A. Vaishnav,Suzanne M. Jonkheer,Andrei Zlobin,Barbara A. Osborne,Sridevi Gottipati,Jon C. Aster,William C. Hahn,William C. Hahn,Michael P. Rudolf,Kalliopi P. Siziopikou,W. Martin Kast,Lucio Miele +14 more
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TLDR
It is shown that oncogenic Ras activates Notch signaling and that wild-type Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo and suggests that it might be a novel therapeutic target.Abstract:
Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wild-type Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wild-type Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.read more
Citations
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Genetics and biology of pancreatic ductal adenocarcinoma
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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
ras Oncogenes in Human Cancer: A Review
TL;DR: It appeared that ras gene mutations can be found in a variety of tumor types, although the incidence varies greatly and some evidence that environmental agents may be involved in the induction of the mutations.
Journal ArticleDOI
Creation of human tumour cells with defined genetic elements
William C. Hahn,William C. Hahn,Christopher M. Counter,Ante S. Lundberg,Ante S. Lundberg,Roderick L. Beijersbergen,Mary W. Brooks,Robert A. Weinberg +7 more
TL;DR: It is shown that the ectopic expression of the telomerase catalytic subunit (hTERT) in combination with two oncogenes results in direct tumorigenic conversion of normal human epithelial and fibroblast cells.
Journal ArticleDOI
A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
Bart De Strooper,Wim Annaert,Philippe Cupers,Paul Saftig,Katleen Craessaerts,Jeff S. Mumm,Eric H. Schroeter,Vincent Schrijvers,Michael S. Wolfe,William J. Ray,Alison Goate,Raphael Kopan +11 more
TL;DR: It is reported that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1.
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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