Changes in p19Arf localization accompany apoptotic crisis during pre-B-cell transformation by Abelson murine leukemia virus.

Transformation by Abelson murine leukemia virus (Ab-MLV) is a multistep process in which growth-stimulatory signals from the v-Abl oncoprotein and growth-suppressive signals from the p19(Arf)-p53 tumor suppressor pathway oppose each other and influence the outcome of infection. The process involves a proliferative phase during which highly viable primary transformants expand, followed by a period of marked apoptosis (called "crisis") that is dependent on the presence of p19(Arf) and p53; rare cells that survive this phase emerge as fully transformed and malignant. To understand the way in which v-Abl expression affects p19(Arf) expression, we examined changes in expression of Arf during all stages of Ab-MLV transformation process. As is consistent with the ability of v-Abl to stimulate Myc, a transcription factor known to induce p19(Arf), Myc and Arf are induced soon after infection and p19(Arf) is expressed. At these early time points, the infected cells remain highly viable. The onset of crisis is marked by an increase in p19(Arf) expression and a change in localization of the protein from the nucleoplasm to the nucleolus. These data together suggest that the localization and expression levels of p19(Arf) modulate the effects of the protein during oncogenesis and reveal that the p19(Arf)-mediated response is subject to multiple layers of regulation that influence its function during Ab-MLV-mediated transformation.