Constitutive activation of NF‐κB and T‐cell leukemia/lymphoma in Notch3 transgenic mice
Diana Bellavia,Antonio F. Campese,Edoardo Alesse,Alessandra Vacca,Maria Pia Felli,Anna Balestri,Antonella Stoppacciaro,Cecilia Tiveron,Laura Tatangelo,Mirella Giovarelli,Carlo Gaetano,Luigi Ruco,Eric S. Hoffman,Adrian Hayday,Urban Lendahl,Luigi Frati,Alberto Gulino,Isabella Screpanti +17 more
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TLDR
In this article, the effects of Notch3 on thymocyte development were evaluated in transgenic mice expressing lck promoter-driven intracellular Notch-3 and showed an increased number of thymocytes, particularly late CD4-8- cells, a failure to down-regulate CD25 in post-CD4−8− subsets and sustained activity of NF-κB.Abstract:
The multiplicity of Notch receptors raises the question of the contribution of specific isoforms to T-cell development. Notch3 is expressed in CD4–8– thymocytes and is down-regulated across the CD4–8– to CD4+8+ transition, controlled by pre-T-cell receptor signaling. To determine the effects of Notch3 on thymocyte development, transgenic mice were generated, expressing lck promoter-driven intracellular Notch3. Thymuses of young transgenics showed an increased number of thymocytes, particularly late CD4–8– cells, a failure to down-regulate CD25 in post-CD4–8– subsets and sustained activity of NF-κB. Subsequently, aggressive multicentric T-cell lymphomas developed with high penetrance. Tumors sustained characteristics of immature thymocytes, including expression of CD25, pTα and activated NF-κB via IKKα-dependent degradation of IκBα and enhancement of NF-κB-dependent anti-apoptotic and proliferative pathways. Together, these data identify activated Notch3 as a link between signals leading to NF-κB activation and T-cell tumorigenesis. The phenotypes of pre-malignant thymocytes and of lymphomas indicate a novel and particular role for Notch3 in co-ordinating growth and differentiation of thymocytes, across the pre-T/T cell transition, consistent with the normal expression pattern of Notch3.read more
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Regulation and Function of NF-κB Transcription Factors in the Immune System
TL;DR: Much progress has been made in the past two years revealing new insights into the regulation and functions of NF-kappaB, and this recent progress is covered in this review.
Patent
Compositions and methods for treating and diagnosing cancer
TL;DR: In this article, the authors presented gene expression profiles associated with solid tumor stem cells, as well as novel stem cell cancer markers useful for the diagnosis, characterization, and treatment of the stem cells.
Journal ArticleDOI
c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma
Andrew P. Weng,John M. Millholland,Yumi Yashiro-Ohtani,Marie Laure Arcangeli,Arthur Lau,Carol Wai,Cristina Del Bianco,Carlos G. Rodriguez,Hong Sai,John W. Tobias,Yue-Ming Li,Michael S. Wolfe,Cathy Shachaf,Dean W. Felsher,Stephen C. Blacklow,Warren S. Pear,Jon C. Aster +16 more
TL;DR: In this article, the authors identified c-myc as a direct target of Notch1 in Notch-dependent T-ALL cell lines, in which Notch accounts for the majority of cmyc expression.
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.
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 ArticleDOI
Activators and target genes of Rel/NF-kappaB transcription factors.
TL;DR: It is argued that NF-κB functions more generally as a central regulator of stress responses and pairing stress responsiveness and anti-apoptotic pathways through the use of a common transcription factor may result in increased cell survival following stress insults.
Journal ArticleDOI
Suppression of TNF-α-Induced Apoptosis by NF-κB
TL;DR: In this paper, the sensitivity and kinetics of TNF-α-induced apoptosis were shown to be enhanced in a number of cell types expressing a dominant negative IkappaBalpha (Ikappa-BalphaM).
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.
Journal ArticleDOI
Deficient T cell fate specification in mice with an induced inactivation of Notch1.
Freddy Radtke,Anne Wilson,G. Stark,Michelle Bauer,Joost P. M. van Meerwijk,H. Robson MacDonald,Michel Aguet +6 more
TL;DR: It is suggested that Notch1 plays an obligatory and selective role in T cell lineage induction in mice with a neonatally induced loss of Notch 1 function.
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