Plasminogen activator inhibitor-2 (PAI-2), a member of the serpin gene family, is thought to serve as a primary regulator of plasminogen activation in the extravascular compartment. High levels of PAI-2 are found in keratinocytes, monocytes, and the human trophoblast, the latter suggesting a role in placental maintenance or embryo development. The primarily intracellular distribution of PAI-2 also may indicate a unique regulatory role in a protease-dependent cellular process such as apoptosis. To examine the potential functions of PAI-2 in vivo, we generated PAI-2-deficient mice by gene targeting in embryonic stem cells. Homozygous PAI-2-deficient mice exhibited normal development, survival, and fertility and were also indistinguishable from normal controls in response to a bacterial infectious challenge or endotoxin infusion. No differences in monocyte recruitment into the peritoneum were observed after thioglycollate injection. Epidermal wound healing was equivalent among PAI-2 ؊͞؊ null and control mice. Finally, crossing PAI-2 ؊͞؊ with PAI-1 ؊͞؊ mice to generate animals deficient in both plasminogen activator inhibitors failed to uncover an overlap in function between these two related proteins.
We report results of experiments in which we demonstrated the existence of a polymerase I promoter within the ribosomal DNA spacer upstream from the rRNA initiation site in Chinese hamsters and mice. Transcription of the CHO spacer promoter was achieved by the same protein factors, C and D, that catalyzed transcription of the gene promoter, and these factors bound stably to the CHO spacer promoter in a preinitiation complex, just as they did to the gene promoter. In contrast to the CHO spacer promoter, which was transcribed in vitro nearly as efficiently as the gene promoter, the mouse spacer promoter was far less active; this low activity was attributable to the fact that the mouse spacer promoter bound factor D inefficiently. It is striking that the active CHO spacer promoter violated the otherwise universal rule that metazoan RNA polymerase I promoters all have a G residue at position -16. Sequence comparisons also revealed a great similarity between the CHO and mouse spacer promoter regions, yet there was much less similarity between the flanking sequences. There was also only limited homology between the spacer and gene promoter regions, but despite this the two kinds of initiation regions were organized similarly, both consisting of an essential core promoter domain and a stimulatory domain that extended upstream to approximately residue -135. Evolutionary considerations argue strongly that the presence of ribosomal DNA spacer promoters offers a significant selective advantage.Although it is frequently stated that the rRNA gene promoter is the only site at which RNA polymerase I initiates transcription, it has been known for several years that the spacer regions separating adjacent rRNA genes in a number of invertebrate and lower vertebrate species contain repeated elements that are related to the gene promoter. In members of the genera Xenopus, Drosophila, and Artemia, the ribosomal DNA (rDNA) spacer contains two to five spacer promoters whose sequences are highly homologous to those of the respective gene promoters and which exhibit promoter activity in vitro, in vivo, or both (1, 12, 18, 19, 27, 29, 32-34, 37, 43). In Xenopus laevis, both the spacer promoters and adjoining 60-and 81-base-pair (bp) repetitive elements, which are duplications of the central region of the gene promoter, have been shown to affect transcription (6,7,36) and recently have been demonstrated to enhance expression from adjoining rRNA gene promoters (L. Pape, J. Windle, and B. Sollner-Webb, submitted for publication). In addition, an intergenic sequence element in yeast rDNA which has been reported to possess promoter activity in vitro (40) also acts as a yeast rRNA gene enhancer element in vivo (9, 10).In part because of its much greater size, the spacer region of mammalian rDNA repeats remains largely uncharacterized. However, the presence of spacer promoters in many diverse lower organisms suggested that such elements may also exist in mammalian spacer regions. While mouse rDNA evidently does not contain spacer promoters with...
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