STRUCTURE AND EXPRESSION OF THE HUMAN FHIT GENE IN NORMAL AND TUMOR-CELLS

The FHIT gene, encoded by 10 exons in a 1.1-kb transcript, encompasses approximately 1 Mb of genomic DNA, which includes the hereditary RCC t(3;8) translocation break at 3p14.2, the FRA3B common fragile region, and homozygous deletions in various cancer-derived cell lines, Becaus e some of these genetic landmarks (e.g., the t(3;8) break between untr anslated FHIT exons 3 and 4, a major fragile region that includes a vi ral integration site between exons 4 and 5, and cancer cell homozygous deletions in intron 5) do not necessarily affect coding exons and yet apparently affect expression of the gene product, se examined the FHI T locus and its expression in detail in more than 10 tumor-derived cel l lines to clarify mechanisms underlying aberrant expression. We obser ved some cell lines with apparently continuous large homozygous deleti ons, which included one or more coding exons; cell lines with disconti nuous deletions, some of which included or excluded coding exons; and cell lines that exhibited heterozygous and/or homozygous deletions, by Southern blot analysis for the presence of specific exons. Most of th e cell Lines that exhibited genomic alterations showed alteration of F HIT transcripts and absence or diminution of Fhit protein.