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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Palomero, Teresa Neuberg, Donna Young, Richard A. Weng, Andrew P. Odom, Duncan T. Lim, Wei Keat Sigaux, Francois Califano, Andrea Real, Pedro J. Soulier, Jean Aster, Jon C. Barnes, Kelly C. Look, A. Thomas Ferrando, Adolfo A. Sulis, Maria Luisa O'neil, Jennifer Margolin, Adam |
| Description | Author Affiliation: Palomero T ( Institute for Cancer Genetics and Joint Centers for Systems Biology, Columbia University, New York, NY 10032, USA.); |
| Abstract | The NOTCH1 signaling pathway directly links extracellular signals with transcriptional responses in the cell nucleus and plays a critical role during T cell development and in the pathogenesis over 50% of human T cell lymphoblastic leukemia (T-ALL) cases. However, little is known about the transcriptional programs activated by NOTCH1. Using an integrative systems biology approach we show that NOTCH1 controls a feed-forward-loop transcriptional network that promotes cell growth. Inhibition of NOTCH1 signaling in T-ALL cells led to a reduction in cell size and elicited a gene expression signature dominated by down-regulated biosynthetic pathway genes. By integrating gene expression array and ChIP-on-chip data, we show that NOTCH1 directly activates multiple biosynthetic routes and induces c-MYC gene expression. Reverse engineering of regulatory networks from expression profiles showed that NOTCH1 and c-MYC govern two directly interconnected transcriptional programs containing common target genes that together regulate the growth of primary T-ALL cells. These results identify c-MYC as an essential mediator of NOTCH1 signaling and integrate NOTCH1 activation with oncogenic signaling pathways upstream of c-MYC. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 48 |
| Volume Number | 103 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2006-11-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Leukemia Metabolism Pathology Proto-Oncogene Proteins C-myc Receptor, Notch1 Transcription, Genetic Genetics Cell Line Cell Proliferation Feedback, Physiological Gene Expression Profiling Gene Expression Regulation, Neoplastic Promoter Regions, Genetic Protein Engineering Signal Transduction Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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