Over the past 4 years we have documented that hypersensitivity to mitotic inhibitory factors accounts, at least in part, for the apoptotic phenotype in FA cells. To date we have focused on elucidating the potential relationship between FANC and elements of the IFN-gamma pathway because of persuasive evidence that this cytokine plays a role in the pathogenesis of acquired aplastic anemia. Regarding the function of the FANC protein, we have made tow discoveries we believe to be of critical importance. First, FAN-C cells constitutively express IFN-dependent genes that induce mitotic arrest and apoptosis in hematopoietic progenitor cells and these mutant cells expresses these genes through signaling pathways that do not involve stat1. Transduction of FAN-C cells fail to phosphorylate stat1 after exposure to IFN-gamma because the normal FANC protein functions as a chaperone to deliver stat1 to the docking sites on the IFN- receptor alpha chain (IFNGR1). These two findings have converged with recently published findings on the anti-apoptotic function of hematopoietic growth factor receptors to lead us to hypothesize that Fanconi anti-apoptotic function of hematopoietic growth factor receptors to lead us to hypothesize that Fanconi progenitor cells are apoptotic not only because of hypersensitivity to mitotic inhibitors, but because they cannot properly transduce anti-apoptotic signals through hematopoietic growth factor receptors. The studies described in this proposal are designed to test three hypotheses. First, that proper stat- mediated signal transduction via hematopoietic growth factors involves the delivery by the FANC protein, of stat molecules to specific receptor chains after ligand binding (this hypothesis forms the basis of Aim 1). Second, that the delivery of phosphorylated stat molecules to cognate binding sites on nuclear DNA also depends upon binding of stat-dimers to FANC protein (Aim 2). Third, that a specific stat1-independent signaling pathway governs; (a) the constitutive expression of p21wf1, IRF-1 and ISGF3-gamma in FAN-C cells and (b) same non-stat pathway accounts for the IFN/TNF/TGF sensitivity of FAN-C cells (Aim 3).
Showing the most recent 10 out of 106 publications
