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.
| Limnander, Andre; Danial, Nika N; Rothman, Paul B (2004) v-Abl signaling disrupts SOCS-1 function in transformed pre-B cells. Mol Cell 15:329-41 |
| Fan, P D; Goff, S P (2000) Abl interactor 1 binds to sos and inhibits epidermal growth factor- and v-Abl-induced activation of extracellular signal-regulated kinases. Mol Cell Biol 20:7591-601 |
| Cong, F; Spencer, S; Cote, J F et al. (2000) Cytoskeletal protein PSTPIP1 directs the PEST-type protein tyrosine phosphatase to the c-Abl kinase to mediate Abl dephosphorylation. Mol Cell 6:1413-23 |
| Cong, F; Yuan, B; Goff, S P (1999) Characterization of a novel member of the DOK family that binds and modulates Abl signaling. Mol Cell Biol 19:8314-25 |
| Cong, F; Goff, S P (1999) c-Abl-induced apoptosis, but not cell cycle arrest, requires mitogen-activated protein kinase kinase 6 activation. Proc Natl Acad Sci U S A 96:13819-24 |
| Cong, F; Zou, X; Hinrichs, K et al. (1999) Inhibition of v-Abl transformation by p53 and p19ARF. Oncogene 18:7731-9 |
