) Frequent homozygous and compound heterozygous deletions in FHIT at 3p14.2, the genome's most fragile site, are found in tumors and cancer cell lines. Fhit protein, the prototypical member of a new family of purine nucleotide-binding proteins, is reduced or undetectable in tumors and cancer cell lines with deletions. Expression of exogenous FHIT in lung, kidney and gastric cancer cell lines lacking endogenous FHIT suppresses tumor formation in nude mice. Thus, Fhit is a potential tumor suppressor for a large fraction of cancers of multiple sites known to involve environmental factors. This Program will investigate the involvement of FHIT in cancer with three Projects, aided by Cores A and B for Administration and Nucleic Acid analysis. Kay Huebner, Program Director and leader of Project 1, will study the function of the Fhit protein, with an emphasis on characterization of interacting proteins, to provide a basis for understanding its role in cancer. Project 2, led by Carlo Croce, will use the sequence of the FHIT gene encompassing the major fragile region to determine precise deletion endpoints in cancer-derived cell lines to clarify mechanisms of breakage at the fragile sites vis a vis environmental factors, and use this information to diagnose breakpoints in early lesions. Charles Brenner, leader of Project 3, will study the recently discovered NitFhit protein, a combined nitrilase-Fhit open reading frame, for clues to function of the NitFhit signaling pathway. He will determine NitFhit crystal structure, use Nit minus yeast cells to trap the Nit substrate and seek inhibitors of Nit function. Cores A and B will provide administration support and nucleic acid analysis which is essential in the three interactive projects. Thus, this focused, yet multidisciplinary Project sees in FHIT opportunities to grapple with some of the most pressing problems of cancer: genetic rearrangement and its relationship to susceptibility; and the molecular and cellular functions of signaling pathways that lead to tumors.
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