We have identified a novel zinc-finger protein whose mRNA is expressed at high levels in the epidermal layer of the skin and in epithelial cells in the tongue, palate, esophagus, stomach, and colon of newborn mice. Expression in epithelial cells is first detected at the time of their differentiation during embryonic development. In addition, during early embryonic development there is expression in mesenchymal cells of the skeletal primordia and the metanephric kidney which is later downregulated. The expression pattern suggests that the protein could be involved in terminal differentiation of several epithelial cell types and could also be involved in early differentiation of the skeleton and kidney. The carboxyl terminus of the protein contains three zinc fingers with a high degree of homology to erythroid krü ppel-like factor and binds to DNA fragments containing CACCC motifs. The amino-terminal portion of the protein is proline and serine-rich and can function as a transcriptional activator. The chromosomal location of the gene was mapped using mouse interspecific backcrosses and was shown to localize to mouse chromosome 4 and to cosegregate with the thioredoxin gene.During embryogenesis, a single-cell zygote gives rise to a complex organism composed of many cell types which differentiate from their precursors in an intricate process involving the coordinate action of various cytokines, hormones, and growth factors which activate the expression of specific transcription factors in the cell. Many cell-specific transcription factors involved in the differentiation of tissues have been identified: these fall into several broad classes that include helix-loophelix proteins, homeodomain proteins, and zinc-finger proteins. Zinc-finger transcription factors generally contain a cluster of zinc-finger motifs which together bind to specific DNA sequences; they can be divided into several classes based on the sequence and position of the cysteine and histidine residues and other conserved amino acids. The TFIIIA subclass of zincfinger proteins is characterized by an amino acid motif (Cys-X 2-4 -Cys-X 12 -His-X 3-4 -His) that coordinates zinc ions and is involved in DNA binding. Some zinc-finger proteins of the

Bisphosphonates are a widely used class of drugs that have been proven to be extremely useful in the prevention and treatment of osteoporosis, hypercalcemia of malignancy, and bone metastases associated with multiple myeloma, breast cancer, and other solid tumors. In the past several years there have been numerous reports describing the occurrence of Osteonecrosis of the Jaws (ONJ) associated with these drugs. In the great majority of cases this condition develops after surgical manipulation of the oral tissues. The natural history and pathophysiology of ONJ however, remains unknown at the present time. Furthermore, whether the ONJ lesion initiates in the oral mucosa or derives from the underlying bone has not been determined. In this report we describe the effect of pamidronate, a second generation bisphosphonate, on oral mucosal cells. Our results show that bisphosphonate pre-treatment of oral mucosal cells inhibits proliferation and wound healing at clinically relevant doses and that this inhibition is not due to cellular apoptosis.

Spi-B is a hematopoietic-specific Ets

It has been shown that mice with a targeted mutation in the Ets-1 gene exhibit increased B cell terminal differentiation to IgM-secreting plasma cells. Here, we show that mice, formerly described to lack Ets-1 protein, actually express low levels of an internally deleted Ets-1 protein. Mice harboring this Ets-1 hypomorphic allele possess very few marginal zone B cells and have increased expression of activation markers on follicular B cells. Adoptive transfer experiments indicate that this activated phenotype can be reversed upon transfer of Ets-1-deficient B cells to a wild-type host, suggesting a role for B cell-extrinsic factors in regulating the activated state. Supporting this observation, the reverse transfer experiment of wild-type B cells into an Ets-1-deficient host resulted in increased expression of activation markers on the transferred B cells. However, there are also cell-intrinsic changes in Ets-1-deficient B cells as demonstrated by their increased differentiation to plasma cells in vitro in response to stimulation with cytosine-phosphate-guanine DNA sequence-containing oligodeoxynucleotide [CpG DNA, a Toll-like receptor (TLR) 9 ligand]. Consistent with the activated phenotype and increased terminal differentiation of Ets-1-deficient B cells, Ets-1 mutant mice develop autoimmune disease. Hence, our studies establish Ets-1 as an important regulator of peripheral B cell differentiation and B cell responses to TLR9 activation.