Upregulation of N-acetylglucosaminyltransferase-V by heparin-binding EGF-like growth factor induces keratinocyte proliferation and epidermal hyperplasia

Oligosaccharide modification by N-acetylglucosaminyltransferase-V (GnT-V), a glycosyltransferase encoded by the Mgat5 gene that catalyses the formation of β1,6 GlcNAc (N-acetylglucosamine) branches on N-glycans, is thought to be associated with cancer growth and metastasis. Overexpression of GnT-V in cancer cells enhances the signalling of growth factors such as epidermal growth factor (EGF) and transforming growth factor-β by increasing galectin-3 binding to polylactosamine structures on receptor N-glycans. We previously demonstrated that transgenic mice overexpressing GnT-V fail to develop spontaneous tumors in any organs, but phenotypes reminiscent of epithelial-to-mesenchymal transition were observed in their skin. However, the biological function of GnT-V in normal skin remained unknown. In this study, we examined the role of GnT-V in keratinocyte proliferation using GnT-V-deficient mice. Proliferation of human keratinocytes was suppressed by treatment with GnT-V siRNA. Mgat5(-/-) mouse keratinocytes also showed impaired cell proliferation through the reduction in EGF receptors on the cell surface. Although the skin of Mgat5(-/-) mice appeared normal, epidermal hyperplasia and proliferation of keratinocytes induced by the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) were downregulated in these mutants. Moreover, a dramatic increase in GnT-V expression was observed by treatment with TPA or heparin-binding EGF-like growth factor (HB-EGF) in normal human epidermal keratinocytes. This increase was inhibited by an EGF receptor inhibitor. These results indicate that a high expression of GnT-V in keratinocytes contributes to HB-EGF-mediated epidermal hyperproliferation by inhibiting endocytosis of EGF receptors bearing β1,6 GlcNAc on their N-glycans. Our findings demonstrate a novel role for GnT-V in epidermal homoeostasis, particularly in hyperproliferative conditions.     

Progestin therapy for endometrial cancer: the potential of fourth-generation progestin (review)

Progestin preparations are made of synthetic progesterone and have often been used for hormone therapy in gynecological patients with endometriosis or endometrial cancer. Hormone therapy using progestin is considered to be one of the effective means of treatment particularly when dealing with endometrial cancer (an estrogen-dependent tumor). Numerous reports have been published concerning its efficacy in advanced or recurrent cases of atypical endometrial hyperplasia or endometrial cancer. Dienogest has been developed as a fourth-generation progestin for hormone therapy for endometriosis that can be used with high safety for long periods of time. In Japan, dienogest has been recommended as a first-line drug for endometriosis-associated pain. However, its antitumor activity has also been attracting close attention following a report that this drug suppressed the proliferation in vitro of endometrial cancer-derived cell lines which failed to respond to other progestins such as medroxyprogesterine acetate (MPA). The mechanism for antitumor activity of dienogest is considered to differ from the mechanism for antitumor activity of conventional progestin preparations used for treatment of endometrial cancer. This drug is expected to be clinically applicable as a new drug for the treatment of endometrial cancer.     

A case of severe Chlamydia pneumoniae pneumonia requiring mechanical ventilation and complicated with disseminated intravascular coagulation]

A previously healthy 48-year-old man presented to his primary care physician with high fever, dry cough and dyspnea. Pneumonia was diagnosed and intravenous administration of imipenem/cilastatin was begun, but his respiratory condition worsened and he was admitted to our hospital with severe hypoxia. A chest radiograph showed reticular opacity and consolidation in both lung fields. The case was complicated with disseminated intravascular coagulation. Analysis of the bronchoalveolar lavage fluid showed increases in the total cell counts and an elevated percentage of lymphocytes. Sputum, blood and bronchoalveolar lavage examinations failed to reveal etiology to explain his severe respiratory illness. Treatment consisted of mechanical ventilation and administration of steroid pulse-therapy and gabexate mesilate. On the basis of his clinical course, we suspected possible atypical pneumonia, and began therapy with intravenous minocyclin and oral erythromycin administration. On the third hospital day, the arterial blood gas data improved and the bilateral pulmonary infiltration on the chest radiographs disappeared. Using paired sera, we detected increases of 1.35 in ID for anti-Chlamydia pneumoniae IgG antibodies by ELISA, and arrived at a diagnosis of Chlamydia pneumoniae pneumonia.     

Acute effect of green tea catechins on uric acid metabolism after alcohol ingestion in Japanese men

Clinical Rheumatology - Alcohol consumption is associated with hyperuricemia and gout. Previous studies have indicated a role for green tea catechins in uric acid (UA) metabolism. This study aimed...     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis

Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder precipitated by coffee, alcohol, and stress. We previously identified the causative gene but the function of the encoded protein remains unknown. We also generated a PNKD mouse model that revealed dysregulated dopamine signaling in vivo. Here, we show that PNKD interacts with synaptic active zone proteins Rab3-interacting molecule (RIM)1 and RIM2, localizes to synapses, and modulates neurotransmitter release. Overexpressed PNKD protein suppresses release, and mutant PNKD protein is less effective than wild-type at inhibiting exocytosis. In PNKD KO mice, RIM1/2 protein levels are reduced and synaptic strength is impaired. Thus, PNKD is a novel synaptic protein with a regulatory role in neurotransmitter release.Paroxysmal nonkinesigenic dyskinesia (PNKD)^* is a rare dominantly inherited episodic movement disorder. First reported in 1940 (1), PNKD is characterized by childhood onset with involuntary movements in the limbs, trunk, and face manifesting as dystonia, chorea, and athetosis (2). PNKD shows nearly complete penetrance and attacks are precipitated by fatigue, stress, hunger, and consumption of coffee or alcohol. Patients are completely normal between attacks.Hereditary forms of many episodic disorders are recognized and include movement disorders, muscle diseases, cardiac arrhythmias, epilepsy, and headache. A majority of the causative genes that have been identified encode ion channels (3). Studies in several spontaneous mouse mutants with a paroxysmal dyskinesia phenotype have provided intriguing insights into these otherwise complicated diseases (4–6). The tottering and lethargic mice display motor abnormalities mimicking paroxysmal dyskinesia and harbor mutations in the genes encoding the α1A and β4 subunits of the P/Q-type voltage-gated Ca²⁺-channel, respectively (7, 8). Like PNKD, the dyskinesia phenotype in tottering mice can also be triggered by caffeine and stress. PNKD is interesting in that the gene encodes a novel protein with homology to human glyoxalase II, an enzyme in a stress-response pathway. Although the normal role of PNKD is unknown, we previously identified the causative gene of PNKD (9) and a mouse model of the human mutations recapitulates the phenotype and shows dopamine signaling dysregulation (10).At synapses, vesicle priming, docking, and fusion at synaptic terminals are complex and coordinately regulated by proteins from the active zone, presynaptic membrane, and vesicles (11). Rab3-interacting molecules (RIMs) are a family of active zone proteins encoded by genes, Rims 1 to 4 (12). Through their interactions with vesicle proteins, active zone proteins, and presynaptic membrane proteins, RIMs are centrally involved in basic parameters of neurotransmitter release, and they contribute to both long-term and short-term synaptic plasticity (13–18).Given that PNKD is a novel protein whose function is unknown, we set out to identify proteins that interact with PNKD to provide clues to its normal function. Here, we show that PNKD is a novel synaptic protein that interacts with RIMs and can be found at presynaptic terminals. RIM1 and RIM2 are known to facilitate exocytosis and wild-type PNKD protein inhibits the RIM-dependent increase of neurotransmitter release. Mice deficient in Pnkd have decreased RIM levels, impaired synaptic facilitation and transmission, and abnormal motor behavior. Thus, PNKD is a novel synaptic protein regulating exocytosis in vitro and in vivo.     

A Discrete Glycinergic Neuronal Population in the Ventromedial Medulla That Induces Muscle Atonia during REM Sleep and Cataplexy in Mice

During rapid eye movement (REM) sleep, anti-gravity muscle tone and bodily movements are mostly absent, because somatic motoneurons are inhibited by descending inhibitory pathways. Recent studies showed that glycine/GABA neurons in the ventromedial medulla (VMM; Gly^VMM neurons) play an important role in generating muscle atonia during REM sleep (REM-atonia). However, how these REM-atonia-inducing neurons interconnect with other neuronal populations has been unknown. In the present study, we first identified a specific subpopulation of Gly^VMM neurons that play an important role in induction of REM-atonia by virus vector-mediated tracing in male mice in which glycinergic neurons expressed Cre recombinase. We found these neurons receive direct synaptic input from neurons in several brain stem regions, including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD; Glu^SLD neurons). Silencing this circuit by specifically expressing tetanus toxin light chain (TeTNLC) resulted in REM sleep without atonia. This manipulation also caused a marked decrease in time spent in cataplexy-like episodes (CLEs) when applied to narcoleptic orexin-ataxin-3 mice. We also showed that Gly^VMM neurons play an important role in maintenance of sleep. This present study identified a population of glycinergic neurons in the VMM that are commonly involved in REM-atonia and cataplexy.SIGNIFICANCE STATEMENT We identified a population of glycinergic neurons in the ventral medulla that plays an important role in inducing muscle atonia during rapid eye movement (REM) sleep. It sends axonal projections almost exclusively to motoneurons in the spinal cord and brain stem except to those that innervate extraocular muscles, while other glycinergic neurons in the same region also send projections to other regions including monoaminergic nuclei. Furthermore, these neurons receive direct inputs from several brainstem regions including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD). Genetic silencing of this pathway resulted in REM sleep without atonia and a decrease of cataplexy when applied to narcoleptic mice. This work identified a neural population involved in generating muscle atonia during REM sleep and cataplexy.     

MiR-200b suppresses TNF-α-induced AMTN production in human gingival epithelial cells

Odontology - Amelotin (AMTN) is an enamel protein that is localized in junctional epithelium (JE) of gingiva and suggested to be involved in the attachment between JE and tooth enamel. MicroRNA is...