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 #
5R01CA083736-14
Application #
8631045
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
2014-04-01
Budget End
2015-03-31
Support Year
14
Fiscal Year
2014
Total Cost
$254,203
Indirect Cost
$88,058
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
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Jin, Ke; Zhou, Wen; Han, Xiaoqing et al. (2017) Acetylation of Mastermind-like 1 by p300 Drives the Recruitment of NACK to Initiate Notch-Dependent Transcription. Cancer Res 77:4228-4237
Han, Xiaoqing; Ranganathan, Prathibha; Tzimas, Christos et al. (2017) Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex. Mol Cancer Res 15:1173-1183
Broadus, Matthew R; Chen, Tony W; Neitzel, Leif R et al. (2016) Identification of a Paralog-Specific Notch1 Intracellular Domain Degron. Cell Rep 15:1920-9
Astudillo, Luisana; Da Silva, Thiago G; Wang, Zhiqiang et al. (2016) The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis. Cancer Res 76:3593-603
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
Bai, Feng; Chan, Ho Lam; Scott, Alexandria et al. (2014) BRCA1 suppresses epithelial-to-mesenchymal transition and stem cell dedifferentiation during mammary and tumor development. Cancer Res 74:6161-72
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
Azzam, Diana J; Zhao, Dekuang; Sun, Jun et al. (2013) Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in ?-secretase inhibitor drug responses. EMBO Mol Med 5:1502-22
Licciulli, Silvia; Avila, Jacqueline L; Hanlon, Linda et al. (2013) Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. Cancer Res 73:5974-84

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