Hyper-activation of proto-oncoprotein c-Abl may cause various forms of leukemia. Evidence suggests that the activity of c-Abl can be downregulated by ubiquitin-dependent degradation of c-Abl. However, molecular mechanisms underlying this process is not clear. The Cbl family of proteins are E3 ubiquitin ligases. They are phosphorylated by c-Abl and associate with c-Abl and other signaling molecules downstream of c-Abl, such as CrkL, p85 of PI-3 kinase and Vav, upon c-Abl activation. Since Cbl proteins promote ubiquitination of the associated molecules, the interplay between these molecules and Cbl proteins may have a significant role in c-Abl signaling required for various cellular functions and cell transformation. ? Our hypothesis is that Cbl proteins negatively regulate c-Abl signaling at two levels: 1) by promoting ubquitination and degradation of the activated c-Abl. 2) by facilitating ubiquitination of c-Abl downstream signaling molecules, such as CrkL, p85PI-3K and Vav. Loss of such regulations may lead to hyperactivation of Abl signaling, and possibly hyperproliferation and malignant transformation of cell. To study this hypothesis, we have generated several mutant strains of mice deficient in either c-Cbl or Cbl-b alone or simultaneously in specific tissues, as well as mice expressing a mutant Cbl that lacks the ubiqutin ligase activity but still retains the multi-adaptor function. Here, we propose to investigate: ? 1) The role and regulatory mechanisms of Cbl proteins in c-Abl signaling. ? 2) The significance of interplay between c-Abl and Cbl proteins in the development of leukemia. Completion of this study will provide insight into the regulatory role of Cbl proteins in Abl signaling and Abl-induced leukemia. It may also provide tools for future prevention and clinic therapy of leukemia. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA112944-02
Application #
7140145
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mufson, R Allan
Project Start
2005-09-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2008-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$202,810
Indirect Cost
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032