fried@cc.ucsf.edu
(415) 502-4334 (voice); (415) 502-3179 (fax)

Box 0128, UCSF; San Francisco, CA 94143-0128

deliveries: 2340 Sutter Street, N-361; San Francisco, CA 94115

Full Biosketch

Juan Arbelaez; Matthew Hart

The current main interest of our lab is the regulation of the ARF-p53 tumor suppressor signaling pathway and its role in mediating oncogene co-operation. Cancer is a multi-step process that can occur through the action of a number of oncogenes acting co-operatively to override the host cell1s regulatory control systems. Some oncogenes stimulate activation of cellular pathways leading to uncontrolled cell division. These inappropriate activation signals usually trigger cellular defense genes, tumor suppressors that neutralize the neoplastic effect of the activating oncogene by causing the cell to stop dividing or die. Other oncogenes that can abrogate the negative effects of these tumor suppressor pathways co-operates with the activating oncogene to generate a dividing cancer cell. Unscheduled growth signals generated by a number of activated oncogenes induce the ARF tumor suppressor protein (specified by the Alternative Reading Frame transcript of the p16 INK4A gene in the CDNK2A Locus). ARF usually activates a p53 response that can lead to a cell cycle arrest or apoptotic cell death. ARF can also affect the cell cycle in a p53-independent manner. Little is known about the ARF pathway or its regulation. The ARF gene is inactivated in many human cancer cells, and mice lacking the ARF gene are quite tumor prone. Thus, it is important to define the ARF signaling pathway.

The main focus of the lab1s research is to determine the mechanism(s) by which ARF is activated by different oncogenes, as well as to elucidate the signaling from ARF that results in the induction of p53 leading to either apotosis or cell cycle arrest. This research effort also involves studying the relationship of the ARF and p53 tumor suppressors in the cell cycle and their involvement in oncogene co-operation. Research projects involve defining the ARF-p53 signaling pathway using biological, biochemical and genetic approaches. A number of viruses encode proteins that inactivate the ARF-p53 tumor suppressor pathway after viral infection. We plan is to use these viral proteins as tools to dissect components of the cellular ARF-p53 tumor suppressor pathway. In this manner we hope to determine the mechanism(s) that the viral proteins use to interfere with the ARF-mediated activation of p53 to better define this important cellular signaling pathway and its role in oncogene co-operation.

In addition to utilizing viruses as tools to disrupt the ARF-p53 signaling pathway we are directly analyzing this cellular pathway in mammalian cells. We are interested in determining post-translational modifications (e.g. phosphorylation) of ARF, p53 and MDM2 and assessing changes in these modifications under conditions where the ARF-p53 pathway is functional and nonfunctional. In addition we are employing genetic screens to identify unrecognized cellular genes involved in the ARF-p53 tumor suppressor signaling pathway. In this way we hope to characterize novel properties of the ARF-p53 tumor suppressor signaling circuit, which can potentially suggest new therapeutic approaches to restoring p53 function and exploit ARF and p53 dysfunction in cancer cells.