Numerous bacterial products such as lipopolysaccharide potently induce type I interferons (IFNs); however, the contribution of this innate response to host defense against bacterial infection remains unclear. Although mice deficient in either IFN regulatory factor (IRF)3 or the type I IFN receptor (IFNAR)1 are highly susceptible to viral infection, we show that these mice exhibit a profound resistance to infection caused by the Gram-positive intracellular bacterium Listeria monocytogenes compared with wild-type controls. Furthermore, this enhanced bacterial clearance is accompanied by a block in L. monocytogenes–induced splenic apoptosis in IRF3- and IFNAR1-deficient mice. Thus, our results highlight the disparate roles of type I IFNs during bacterial versus viral infections and stress the importance of proper IFN modulation in host defense.

Toll-like receptor (TLR) signaling and phagocytosis are hallmarks of macrophage-mediated innate immune responses to bacterial infection. However, the relationship between these two processes is not well established. Our data indicate that TLR ligands specifically promote bacterial phagocytosis, in both murine and human cells, through induction of a phagocytic gene program. Importantly, TLR-induced phagocytosis of bacteria was found to be reliant on myeloid differentiation factor 88-dependent signaling through interleukin-1 receptor-associated kinase-4 and p38 leading to the up-regulation of scavenger receptors. Interestingly, individual TLRs promote phagocytosis to varying degrees with TLR9 being the strongest and TLR3 being the weakest inducer of this process. We also demonstrate that TLR ligands not only amplify the percentage of phagocytes uptaking Escherichia coli , but also increase the number of bacteria phagocytosed by individual macrophages. Taken together, our data describe an evolutionarily conserved mechanism by which TLRs can specifically promote phagocytic clearance of bacteria during infection.

The human BRCA1 tumor suppressor interacts with transcriptional machinery, including RNA polymerase II (RNA pol II). We demonstrated that interaction with RNA pol II is a conserved feature of BRCA1 proteins from several species. We found that full-length BRCA1 proteins universally fail to activate transcription in classic GAL4-UAS one-hybrid assays and that the activity associated with the human BRCA1 C terminus was poorly conserved in closely related homologs of the gene. Fractionation studies demonstrated that BRCA1 proteins from all species tested interacted specifically with hyperphosphorylated pol II (IIO), in preference to hypophosphorylated RNA pol II (IIA) expected at promoters. BRCA1-RNA pol II complexes showed evidence of a multiply phosphorylated heptad repeat domain in the catalytic subunit (p220) of RNA pol II, and the complex was highly functional in transcriptional run-off assays. Interestingly, endogenous BRCA1 associated with a large fraction of the processive RNA pol II activity present in undamaged cells, and the interaction was disrupted by DNA-damaging agents. Preferential interaction with processive RNA pol II in undamaged cells places BRCA1 in position to link late events in transcription with repair processes in eukaryotic cells.Mutations in the BRCA1 tumor suppressor gene are associated with an increased risk of breast and ovarian cancer and an elevated incidence of certain other cancers (1-3). Genetic and biochemical data place BRCA1 as a downstream target of ATM/ ATR in cellular responses to genotoxic stress, and the BRCA1 protein has been implicated in chromatin remodeling and homologous recombination functions in mitotic and meiotic cells (4 -8). BRCA1 complexes contain E3 ubiquitin-ligase activity, but the precise target(s) remains an avenue of active study (9, 10). Although BRCA1 proteins show surprisingly low sequence identity, human BRCA1 can replace the mouse gene in genetically engineered animals (11, 12), a result that implies general conservation of important functional motifs. Comparative functional studies are thus likely to play an important role in identifying critical targets of BRCA1 in human cells.A distinct literature has evolved linking BRCA1 to roles in transcription. BRCA1 protein has been shown to associate with RNA polymerase II (RNA pol II) 1 and various transcriptional regulators (13). Early on, several groups demonstrated that the C-terminal domain (CTD; amino acids 1380 -1863) of human BRCA1 scored positively in transcriptional activator trap experiments using various forms of the so-called "one-hybrid" assay (14 -18). While not elucidating a specific function, ectopic expression of full-length human BRCA1 was then shown to increase expression of stress-responsive genes including p21 (19), GADD45 (20), and p27 (21) and decreased expression of other genes, including c-Myc-regulated genes (22) and certain estrogen-regulated genes (23). However, it remains an open question whether endogenous BRCA1 directly mediates recruitment of RNA pol II to promoters of these...

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We have cloned the RAG-1 promoter region and have determined that almost all detectable promoter activity resides within a 208-bp fragment. Sequence analysis of this promoter region has identified potential recognition motifs for a number of lymphocyte-restricted and ubiquitous transcription factors. Subsequent assays have revealed that the NF-Y transcription factor interacts with a CCAAT site within the RAG-1 promoter and appears to play an important role in the positive transcriptional regulation of this gene.

The ornate shrew (Sorex ornatus) is restricted to the vanishing wetlands of California, USA and Baja California, Mexico. Several subspecies of ornate shrews are considered ‘mammal species of special concern’ in California by the Department of Fish and Game, and one (Sorex ornatus relictus) has recently been listed as endangered. Populations of shrews around Buena Vista Lake have been diminished or extirpated due to habitat deterioration and human development. In order to study the patterns of genetic variation in isolated populations of Buena Vista Lake shrews, we developed 10 polymorphic microsatellite loci. There were 6–27 alleles per locus, and the loci had heterozygosity values that ranged from 20 to 80%. In addition, we screened 20 different populations of S. ornatus, eight species within two subfamilies of shrews (Soricinae and Crocidurinae), as well as in a mole (Talpidae, Neurotrichus gibbsii), to determine if these loci could be informative in other species as well.