This study describes experiments to determine the functions of the Abi-l (Abelson interactor-1) protein in oncogenic transformation by the Abelson oncoproteins v-Abl and BCR-ABL. The Abelson gene encodes a cytoplasmic tyrosine kinase; v-Abl is an activated form expressed by the Abelson murine leukemia virus, causing a pre-B lymphoma in mice, which BCR-ABL is a less potent version responsible for chronic myelogenous leukemia (CML) and, sometimes, acute lymphocytic leukemia (ALL) in humans. Abi-l was originally identified using the yeast two-hybrid system as a novel SH3 protein that binds to the proline-rich C terminal tail of v-Abl and suppresses its transforming activity. Genetic and biochemical experiments will be performed to determine which signal transduction pathways are controlled or inhibited by the Abi-1 protein or inhibited by the Abi-1 proteins. Cell lines expressing high levels of either the wild-type or mutant Abi-1 will be examined for activation of downstream target genes (c-myc, DHFR); for activation of downstream target genes (c-myc, DHFR): for activation of known PDGF pathways (Ras, PLCg, PI3K); for stimulation of cell cycle regulatory proteins; and for phosphorylation and activation of Jak/Stat and Crkl proteins. Human tumor samples from CML patients will be tested to determine the level of Abi-1 protein, and the fraction bound to BCR-ABL. Finally, mutants of v- Abl will be generated that transforming activity. The yeast two-hybrid system will be used to isolate mutants that bind to one partner but not to others, and viruses carrying the relevant mutations will then be tested for transforming activity in cell lines and mice. These experiments should help identify which of the various pathways emanating from the Abl kinase are required for oncogenic transformation. These experiments may provide important information about the induction and progression of disease in human CML and ALL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA075399-03
Application #
6414829
Study Section
Project Start
2001-01-29
Project End
2001-12-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032