FHIT was initially named the fragile histone triad gene based on its location at the chromosome 3p Fra3B locus that provides one of the most common neoplasia-associated human genomic fragile sites. FHIT is highly expressed in brain, with robust expression in and localized in regions that include hippocampus. The high levels of brain expression of FHIT protein and its characterization as the major human enzyme that can hydrolyze diadenosine-polyphosphates provides a strong link to purinergic signaling [263]. Diadenosine polyphosphates are released from synaptic vesicles along with more classical tranasmitters. They can activate P2Y(1), P2Y(2), and P2Y(4) receptors, homomeric P2X(1), P2X(2), P2X(3), P2X(4), and P2X(6) receptors, and even a P4 receptor-operated Ca++ channel [261]. Recent reports have also implicated FHIT in a nonenzymatic function, altering expression of the cell adhesion related protein beta catenin [264]. Robust inhibition of FHIT’s diadenosine triphosphatase activity by suramin provides a starting place for developing more selective inhibitors [265, 266]. However, recent identification of FHIT as a modulator of beta catenin-induced transcriptional regulation may also place this gene in the cell adhesion signaling cascade as well [263].
