Substantial evidence has demonstrated a role for the Notch gene family in multiple human cancers, including neoplasms of the lymphoid system, pancreas, breast and CMS, among others. However, the pathophysiological mechanism of Notch function remains poorly understood. Deregulation of the Notch signal transduction pathway can drive the neoplastic conversion of cells, playing an important role in both the initiation and maintenance of the transformed state. This transforming activity is an intrinsic property of Notch, which mediates its effects through a transcriptional cascade. The underlying hypothesis of this proposal is that Notch is a scaffold protein that mediates its function through the assembly of a transcriptional regulatory complex(s), which governs changes in gene transcription. Our goal is to characterize the molecular mechanisms regulating the assembly and stability of Notch complexes and Identifying mechanisms that mediate and/or regulate Notch function to better understand Notch signaling in normal and pathological conditions. Our preliminary data demonstrate that assembly and stability of Notch activation complex is regulated by Notch multimerization, phosphorylation and binding to other proteins. These mechanisms may regulate Notch activity through timing of the complex assembly, stabilization of the protein and/or differential activation of Notch targets.
Specific aims for this proposal include;i) characterization of the critical parameters that regulate Notch multimerization and transcriptional complex assembly, ii) characterization of the role of a novel Notch-binding protein termed NACK (Notch Activation Complex Kinase) in Notch activity, and iii) characterization of posttranslational modifications of Notch that play a role in its transcriptional activity regulatio. The long-range goal for these studies is to obtain a comprehensive understanding of how Notch activity transforms cells in order to contribute to the rational design of cancer therapeutics.

Public Health Relevance

Notch has been implicated in multiple human cancers, including neoplasms of the lymphoid system, pancreas, breast and CMS, among others. However, despite the involvement of Notch in the initiation and maintenance of tumors the molecular mechanisms of Notch activity are still poorly understood. The goal of this research proposal is to unveil these mechanisms and determine how Notch activity transforms cells in order to contribute to the rational design of cancer therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA083736-12A1
Application #
8323035
Study Section
Special Emphasis Panel (ZRG1-OBT-J (02))
Program Officer
Mufson, R Allan
Project Start
1999-12-01
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
12
Fiscal Year
2012
Total Cost
$262,065
Indirect Cost
$90,781
Name
University of Miami School of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Weaver, Kelly L; Alves-Guerra, Marie-Clotilde; Jin, Ke et al. (2014) NACK is an integral component of the Notch transcriptional activation complex and is critical for development and tumorigenesis. Cancer Res 74:4741-51
Wang, Zhiqiang; Da Silva, Thiago G; Jin, Ke et al. (2014) Notch signaling drives stemness and tumorigenicity of esophageal adenocarcinoma. Cancer Res 74:6364-74
Ranganathan, Prathibha; Vasquez-Del Carpio, Rodrigo; Kaplan, Fred M et al. (2011) Hierarchical phosphorylation within the ankyrin repeat domain defines a phosphoregulatory loop that regulates Notch transcriptional activity. J Biol Chem 286:28844-57
Demarest, Renee M; Dahmane, Nadia; Capobianco, Anthony J (2011) Notch is oncogenic dominant in T-cell acute lymphoblastic leukemia. Blood 117:2901-9
Ranganathan, Prathibha; Weaver, Kelly L; Capobianco, Anthony J (2011) Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer 11:338-51
Vasquez-Del Carpio, Rodrigo; Kaplan, Fred M; Weaver, Kelly L et al. (2011) Assembly of a Notch transcriptional activation complex requires multimerization. Mol Cell Biol 31:1396-408
Hanlon, Linda; Avila, Jacqueline L; Demarest, Renee M et al. (2010) Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma. Cancer Res 70:4280-6
Rustighi, Alessandra; Tiberi, Luca; Soldano, Alessia et al. (2009) The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer. Nat Cell Biol 11:133-42
Beverly, L J; Ascano, J M; Capobianco, A J (2006) Expression of JAGGED1 in T-lymphocytes results in thymic involution by inducing apoptosis of thymic stromal epithelial cells. Genes Immun 7:476-86
Carlson, Timothy R; Yan, Yibing; Wu, Xiaoqing et al. (2005) Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci U S A 102:9884-9

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