Bolstered by the overexpression of Id proteins in a wide range of human tumors and the frequent correlation with a poor prognosis, several investigators have suggested that Id proteins play key roles in the initiation and progression of cancer. Our own work identified the Retinoblastoma tumor suppressor pathway as a network that cross talks with Id proteins during development but is subverted by Id in Myc-driven cancer. However, the post-translational machinery that regulates Id proteins in normal cells is unknown. Similarly, it remains unclear whether genetic alterations leading to deregulated Id activity exist in cancer cells. Recently, we discovered that colon cancer cells acquire a missense mutation in the Id2 gene that converts Threonine-27 into the unphosphorylatable amino acid Alanine. We also found that Threonine-27 is phosphorylated by the Dyrk1 kinases in vitro and in vivo.
Our Specific Aims will focus on the regulation and function of this phosphorylation event and the destruction signals that we recently identified in Id proteins. Thus, we will define the signaling pathways converging on Threonine-27 phosphorylation and elucidate how they regulate Id2 protein function. Through biochemical and genetic approaches we will also determine why tumor cells select for the Threonine-27 to Alanine Id2 mutant protein. To address this problem in the context of the whole organism, we will generate knock-in mice that conditionally express the tumor-specific mutation of Id2. Finally, we will take advantage of state-of-the-art mass spectrometry approaches developed in our laboratory to identify and characterize novel enzymes responsible for post-translational modifications of Id proteins. Through the proposed work, we aim to provide a better understanding of the post-translational regulatory machinery for Id proteins and unravel new layers of intervention targeting the alteration of this machinery in human cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127643-05
Application #
8196902
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Spalholz, Barbara A
Project Start
2007-12-03
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$324,053
Indirect Cost
$122,778
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Niola, Francesco; Zhao, Xudong; Singh, Devendra et al. (2013) Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis. J Clin Invest 123:405-17
Frattini, Veronique; Trifonov, Vladimir; Chan, Joseph Minhow et al. (2013) The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet 45:1141-9
Niola, Francesco; Zhao, Xudong; Singh, Devendra et al. (2012) Id proteins synchronize stemness and anchorage to the niche of neural stem cells. Nat Cell Biol 14:477-87
Coma, Silvia; Amin, Dhara N; Shimizu, Akio et al. (2010) Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F. Cancer Res 70:3823-32