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Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18261-6. Epub 2006 Nov 17.

NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.

Author information

1
Institute for Cancer Genetics and Joint Centers for Systems Biology, Columbia University, New York, NY 10032, USA.

Erratum in

  • Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4240.

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.

PMID:
17114293
PMCID:
PMC1838740
DOI:
10.1073/pnas.0606108103
[Indexed for MEDLINE]
Free PMC Article

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