Multiple genetic steps that result in the deregulation of two tumor suppressor pathways, governed by the p53 and retinoblastoma (Rb) tumor suppressors, pave the road to cancer in humans. Two proteins encoded by the INK4a/ARF locus, p16INK4a and p19ARF, functionally target the Rb and p53 tumor suppressors, respectively. These four proteins are among the most frequently affected genes in human cancer. We are interested in understanding the individual contribution of these proteins to the development of human cancers and how they may be regulated by upstream signals. Mounting evidence from our lab suggests that the ARF-p53-Mdm2 pathway is not be strictly linear, opening the door for further research into other ARF functions within the nucleolus. The uniqueness of ARF resides in its nucleolar localization, a property that underlies its most basic tumor suppressive function. My lab is using biochemical and proteomic techniques to identify all protein components of the nucleolus in order to study the nucleolar dynamics of ARF tumor suppression. Related to this goal, we have identified several nucleolar oncoproteins involved in various aspects of ribosome biogenesis. Our goal is to understand the basic mechanisms behind ARF’s tumor suppressive capabilities and to relate these processes to our growing knowledge of human cancer progression.