COAMPLIFICATION OF A NOVEL CYCLOPHILIN-LIKE GENE (PPIE) WITH L-MYC INSMALL-CELL LUNG-CANCER CELL-LINES

Specific genetic alterations affecting proto-oncogenes of the myc gene family are frequently detected in human lung cancer. Among 11 SCLC ce ll lines with L-myc gene amplification, four were found to have altera tion of the RLF gene by Southern blot and RT-PCR analyses. One cell li ne, NCI-H378, contained aberrantly-sized L-myc-hybridizing bands by So uthern and Northern blot hybridization but had no alteration of RLF: S ome L-myc-hybridizing cDNAs from NCI-H378 contained a novel sequence w ith close homology to the cyclophilins joined to antisense L-myc exon 2 sequence. Full length cDNAs isolated from human skeletal muscle cont aining only the novel sequence identify open reading frames of 301 and 296 amino acids and differ in the C-terminal region by 22 and 17 amin o acids. This gene, tentatively named PPIE (peptidyl-prolyl cis-trans isomerase E), has 83% amino acid identity with the central conserved r egion of cyclophilin A, is evolutionarily conserved by Southern blot, and exhibits differential tissue expression with highest levels found in muscle and brain. Coamplification of PPIE was observed in seven of eleven L-myc amplified cell lines. Analysis of radiation hybrids sugge sts that the gene order is RLF-PPIE-L-myc on chromosome Ip and pulse-f ield gel electrophoresis localizes all three genes to an 800 megabase Mlu I fragment. The prognostic and functional consequences of PPIE gen e amplification in SCLC can now be determined.