Group A Streptococcus pyogenes (GAS) possesses surface-located fibronectin (Fn)-binding proteins, known to be major adhesion/invasion molecules. Herein, we present two novel Fn-binding proteins of GAS isolated from patients with toxic shock-like syndrome. Using genome sequence databases, the open reading frames for each were identified among the list of putative surface proteins, and they were designated FbaA and FbaB. Fba proteins were expressed on the cell surface of GAS, and recombinant Fba proteins exhibited strong Fn-binding abilities. Further, Fba protein-deficient mutant strains showed significantly lower levels of adhesion and invasion with human epithelial cells as compared to the wild-type. These findings indicate that Fba proteins are involved in the development of invasive streptococcal diseases. In addition, previous results have suggested that streptococcal C5a peptidase (ScpA) protects GAS from phagocytosis by degrading the complement C5a. However, it remains unclear how S. pyogenes recognizes and binds to C5a. In the present study, we identified a C5a-binding protein of GAS, and a search of genome databases revealed that it is identical to the streptococcal plasmin receptor (Plr), also known as streptococcal surface dehydrogenase (SDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We identified a novel function of this multifunctional protein, and our results also indicate that soluble Plr/SDH/GAPDH captures C5a, thus inhibiting its chemotactic function. In addition, both cell-associated Plr/SDH/GAPDH and ScpA were found to be necessary for the cleavage of C5a on the bacterial surface. These re-sults suggest that Plr/SDH/GAPDH mediates the ability of GAS to escape detection by the immune system.

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Oral squamous cell carcinoma (SCC) shows frequent metastasis and recurrence, ultimately with a poor outcome. The long-term survival rates of patients with oral SCC have not significantly been improved. The p53 tumor suppressor gene is known to be one of the most commonly mutated genes in human cancers, including oral SCC. p53 gene replacement therapy to treat such cancers has become an intensive area of research. However, the introduction of wild-type p53 protein is unable to induce apoptosis in all tumor cases, at least in part, due to their resistance to exogenous p53. Recently, we reported that a defect in the phosphorylation of p53 protein at serine 46, which is critical for p53-mediated apoptosis, is responsible for the acquisition of resistance to p53 gene transfer in oral SCC cells. In this review, we focus on the regulation of Ser46 phosphorylation and discuss the contribution of its dysregulation to resistant mechanisms against p53 gene transfer in oral SCC.

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Reactive oxygen species (ROS) have been implicated in the regulation of signal transduction. ROS lead to a wide variety of cellular responses through the activation of various signal transduction pathways. Several protein kinases are known to be activated by ROS, and contribute to the induction of ROS-dependent cellular responses. However, the molecular mechanisms by which ROS induce the activation of these protein kinases are poorly understood. Apoptosis signal-regulating kinase 1 (ASK1) is an ROS-responsive protein kinase that belongs to the mitogen-activated protein kinase kinase kinase (MAP3K)family. The molecular mechanism of ASK1 activation induced by ROS has been well-characterized, and endogenous ASK1 constitutively forms a mega-complex that functions as a signalosome which causes the ROS-dependent activation of ASK1. On the other hand, it has been demonstrated that several inflammatory mediators such as tumor necrosis factor α (TNFα), lipopolysaccharide (LPS), and extracellular ATP (eATP) activate ASK1 in an ROS-dependent manner. Analyses of ASK1-deficient mice have revealed that the ROS-dependent activation of ASK1 plays a pivotal role in inflammatory mediator-induced cellular responses. This review describes recent studies on the molecular mechanism of ROS-dependent activation of ASK1 and its roles in inflammatory signaling.

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The p300 and closely related CREB-binding protein (CBP) acetyltransferases function as global transcriptional coactivators and play important roles in a broad spectrum of biological processes, including cell proliferation, differentiation, and apoptosis. The role of p300/CBP in tumor suppression has been proposed based on the fact that these coactivators are targeted by viral oncoproteins, and that mutations of p300/CBP associated with inactivation of the second allele have been identified in certain types of carcinoma. However, the mechanisms by which the inactivation of p300/CBP contributes to carcinogenesis have not been fully elucidated. In this review, we focus on the understanding of p300 function in tumor suppression, particularly with regard to its relationship with the TGF-β-dependent transcriptional response, which is important for the negative growth regulation of epithelial cells, and also discuss the effects of p300 mutation on the p53 pathway and cell proliferation.

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Application of styryl pyridinium dyes FM1-43 and AM1-43 to a variety of tissues and cells results in bright staining of sensory nerves and cells in dental pulp, periodontal ligament, and gingiva, as well as palatal rugae, hair follicle, gastrointestinal tract, urinary bladder, dorsal root ganglion and trigeminal ganglion. AM1-43 is especially useful for morphological examination, because the sample can be fixed with formaldehyde solution and can be demineralized with ethylenediamine-N, N, N′, N′-tetraacetic acid (EDTA). Internalization mechanism of these dyes into cells is considered to be the passage via nonselective cation channels such as TRPV1, although further examination is needed. Electron microscopic examination of FM1-43 is possible, where a photoconversion method can be applied and the fluorescent dye localizes as electron-dense precipitates. Thus, FM1-43 and AM1-43 are expected to be used widely for in vivo exploration of sensory innervation in dental and craniofacial tissues of a variety of small animals.

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It is unclear which factors in saliva contribute to its rheological properties such as viscosity and spinnbarkeit. In this study, we investigated relationships between the rheological properties (viscosity and spinnbarkeit) and two salivary mucin (MUC5B and MUC7) levels in saliva. Unstimulated (UWS) and chew-ing-stimulated (CWS) whole saliva were collected from healthy young adults, and the viscosities and spinnbarkeits were measured. The image densities of MUC5B and MUC7 bands in saliva were measured by Stains-All staining after electrophoresis. Both the viscosity and spinnbarkeit of UWS were significantly higher than those of CWS. The viscosities were correlated positively with the spinnbarkeit in UWS, but not in CWS. Image-density analysis of mucins demonstrated that the viscosities increased with the levels of MUC5B and the spinnbarkeit with the levels of MUC7. These results suggest that MUC5B contributes to viscosity and MUC7 to spinnbarkeit.

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