v-Abl tyrosine kinase in signal transduction and cell cycle regulation

The v-abl oncogene of Abelson murine leukemia virus (A-MuLV) encodes a deregulated form of the cellular nonreceptor tyrosine kinase. v-Abl activates c-myc transcription, and c-Myc is an essential downstream component in the v-Abl transformation program. This thesis work explores the mechanism by which v-Abl activates c-myc transcription. I show that E2F site in the c-myc promoter is a v-Abl response element and that v-Abl induces c-myc by initiating a phosphorylation cascade that involves Ras, Raf and cyclin-dependent kinases (Cdks), which ultimately activates E2F-binding proteins. I also investigated v-Abl's effects on p27Kip1 cyclin-dependent kinase inhibitor. I show that v-Abl's ability to overcome density arrest in fibroblasts correlates with the downregulation of p27Kip1. Furthermore, this v-Abl-induced p27Kip1 downregulation occurs posttranscriptionally and involves ubiquitin-dependent degradation. Finally, I studied the role of p53 in v-Abl-dependent transformation both in vivo and in vitro by using p53-deficient mice or cells. We show that loss of p53 function can facilitate the A-MuLV induced cell transformation and tumorigenesis. However, p53-dependent mechanism(s) are not primarily responsible for determining the pre-B cell tropism of the A-MuLV.