The overarching goal of this program is to elucidate fundamental properties of Notch signaling that are central to the pathogenesis of cancer. The Notch pathway is one of perhaps 15 or so signaling pathways that regulate development and tissue homeostasis in metazoan animals and which are frequently deranged in human diseases, including cancer. The clearest example of an oncogenic role for Notch is in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), in which gain-of-function Notchl mutations are common. Notchl is a compelling rational therapeutic target in T-ALL, but attempts to treat T-ALL patients with Notch inhibitors to date have been unsuccessful. Thus, it is apparent that more basic and translational research is needed if Notch-directed therapies are to be effective. With this need in mind, Projects 1 and 2 of this Program have complementary aims focused on filling critical gaps in our basic understanding of how Notchl activates its target genes, which are ultimately responsible for driving T-ALL cell growth and survival. The specific overall objectives of Project 1 and Project 2 are: 1. To determine how Notchl regulates the genomes of T-ALL cells 2. To determine how Notchl regulates the genomes of normal thymocytes The mutations in Notchl that lead to T-ALL often result in ligand-independent proteolysis and receptor activation, but such mutations are rare to non-existent in other cancers. On the other hand, there is abundant evidence that ligand-mediated Notch receptor activation has important roles in cancer, both within tumor cell populations and benign stromal elements, such as endothelial cells and immune cells. Thus, understanding how ligands activate Notch receptors has broad cancer relevance, yet many basic aspects of the events underlying ligand-mediated Notch activation remain unknown. Project 3 will address major gaps in current knowledge by pursuing the following objectives: 3. To test the hypothesis that mechanical force is responsible for Notch receptor activation 4. To understand the molecular "logic" of ligand endocytosis, an event that is essential for activation of Notch receptors by ligands The goals of the program will be reached in part with the support of a new Bioinformatics Core (Core B) led by Dr. Shirley Liu, an investigator with a strong background in informatics approaches to understanding cancer epigenetics.

Public Health Relevance

The cohesive, highly interactive nature of our Program and the rich research environments of its host institutions will support the achievement of these objectives, which promise to address important questions of broad relevance to cancer and other diseases in which Notch signaling has been implicated. By meeting these objectives Program will drive conceptual and molecular advances needed for more precise and effective targeting of the Notch pathway in a variety of human maladies, including cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA119070-06A1S1
Application #
8604178
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (J1))
Program Officer
Mufson, R Allan
Project Start
2005-12-01
Project End
2017-06-30
Budget Start
2012-08-31
Budget End
2013-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$58,609
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Stein, Sarah J; Mack, Ethan A; Rome, Kelly S et al. (2016) Trib2 Suppresses Tumor Initiation in Notch-Driven T-ALL. PLoS One 11:e0155408
Bernasconi-Elias, P; Hu, T; Jenkins, D et al. (2016) Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35:6077-6086
Chiang, Mark Y; Wang, Qing; Gormley, Anna C et al. (2016) High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia. Blood 128:2229-2240
Guo, Bingqian; McMillan, Brian J; Blacklow, Stephen C (2016) Structure and function of the Mind bomb E3 ligase in the context of Notch signal transduction. Curr Opin Struct Biol 41:38-45
McMillan, Brian J; Tibbe, Christine; Jeon, Hyesung et al. (2016) Electrostatic Interactions between Elongated Monomers Drive Filamentation of Drosophila Shrub, a Metazoan ESCRT-III Protein. Cell Rep 16:1211-7
Xu, Xiang; Choi, Sung Hee; Hu, Tiancen et al. (2015) Insights into Autoregulation of Notch3 from Structural and Functional Studies of Its Negative Regulatory Region. Structure 23:1227-35
McMillan, Brian J; Schnute, Björn; Ohlenhard, Nadja et al. (2015) A tail of two sites: a bipartite mechanism for recognition of notch ligands by mind bomb E3 ligases. Mol Cell 57:912-24
Wang, Hongfang; Zang, Chongzhi; Liu, X Shirley et al. (2015) The role of Notch receptors in transcriptional regulation. J Cell Physiol 230:982-8
Gordon, Wendy R; Zimmerman, Brandon; He, Li et al. (2015) Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch. Dev Cell 33:729-36
Wang, Hongfang; Zang, Chongzhi; Taing, Len et al. (2014) NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers. Proc Natl Acad Sci U S A 111:705-10

Showing the most recent 10 out of 52 publications