c-Abl is a nuclear tyrosine kinase whose function has remained elusive. It is reported to bind to DNA and bind to Rb and p53. The kinase activity is stimulated by DNA damage, leading to activation of the stress kinase pathway. The goal of this application is to understand the function of c-Abl as a growth inhibitor. By mutagenesis, specific functions of Abl require for the cytostatic response (DNA and p53 binding) will be tested. The effect o c-abl on inhibition of cyclins, cdk activity and CKIs will be examined and causality of the effects will be demonstrated by use of specific knock-out cells. Inducible expression will be used to define where in the abl effects maps within G1 phase. Finally, primary abl-/- fibroblasts (before and after rescue with selected abl constructs) will be used to assess the role of c-abl in growth arrest induced by DNA damage.
