The murine urokinase-type plasminogen activator (uPA) gene has been isolated from a BALB/c liver DNA cosmid library and its nucleotide sequence established. The gene is organized into 11 exons comprising 34.7% of the 6710 base pair (bp) region spanning the interval between the presumed transcription initiation and polyadenylation sites. The transcription initiation site is flanked by common RNA polymerase II promoter elements, including a TATA box and a potential transcription factor Sp1 binding site. A large polypurine tract of the structure (AG)22(AGGG)16(AG)28 is located 79 bp upstream of the 5'-terminus. It was highly sensitive to the single-strand-specific nuclease S1, suggesting a non-B-DNA conformation of unknown significance. Consistent with the well-documented influence of adenosine cyclic 3',5'-phosphate (cAMP) on uPA gene expression, there is a dodecanucleotide homologous to proposed regulatory sequences identified in other cAMP-modulated genes. Comparison of the murine uPA gene to the previously described porcine and human uPA genes revealed an unusually high degree of evolutionary (interspecies) sequence conservation that was not limited to exons but included introns and flanking sequences as well.
Hepatocyte-directed production of urokinase-type plasminogen activator (uPA) in transgenic mice is hepatotoxic. Infrequently, hepatocytes arise that do not express uPA, due to physical loss of transgene DNA, and these cells clonally repopulate the entire liver within 3 months of birth. Surprisingly, hepatic tumors appear in these mice beginning at 8 months of age despite the fact that uPA is not oncogenic or genotoxic. Analysis of the transgene locus reveals that tumors arise only from a particular subclass of transgene-deficient cells in which the entire transgene array, and possibly a significant amount of flanking DNA, is deleted. Considering that all transgene-deficient regenerative nodules undergo extensive replication but only a subset gives rise to tumors, we propose that loss of genomic DNA, not mitogenesis per se, is a primary carcinogenic determinant in this model of hepatocarcinogenesis.
The t(21;22) translocation represents a new cytogenetic abnormality that may be associated with Ewing sarcoma. Its prognostic significance, if any, remains to be determined.
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