Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 121, Issue 2, Pages 800-808Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI43114
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Funding
- NIH/NCI [U24CA83060]
- NIH/NCI In vivo Cellular and Molecular Imaging Center (ICMIC) [P50CA094056]
- Alvin J. Siteman Cancer Center at Washington University, NCI Comprehensive Cancer Center (NIH) [P30CA91842]
- NIH [R01DK066408]
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The role of the Notch signaling pathway in tumor development is complex, with Notch1 functioning either as an oncogene or as a tumor suppressor in a context-dependent manner. To further define the role of Notch1 in tumor development, we systematically surveyed for tumor suppressor activity of Notch1 in vivo. We combined the previously described Notch1 intramembrane proteolysis-Cre (Nip1::Cre) allele with a foxed Notch1 allele to create a mouse model for sporadic, low-frequency loss of Notch1 heterozygosity. Through this approach, we determined the cell types most affected by Notch1 loss. We report that the loss of Notch1 caused widespread vascular tumors and organism lethality secondary to massive hemorrhage. These findings reflected a cell-autonomous role for Notch1 in suppressing neoplasia in the vascular system and provide a model by which to explore the mechanism of neoplastic transformation of endothelial cells. Importantly, these results raise concerns regarding the safety of chronic application of drugs targeting the Notch pathway, specifically those targeting Notch1, because of mechanism-based toxicity in the endothelium. Our strategy also can be broadly applied to induce sporadic in vivo loss of heterozygosity of any conditional alleles in progenitors that experience Notch1 activation.
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