The Wnt protein Wingless (Wg) functions as a signal in patterning of both the Drosophila embryo and imaginal discs. Lack of porcupine (porc) activity is associated with mutant phenotypes similar to those of wg mutations. In porc mutant embryos, Wg protein is confined to the cells that produce it, suggesting that Porc plays a role in processing or secretion of Wg. porc encodes a novel transmembrane protein that appears to be concentrated at the endoplasmic reticulum. We present both genetic and in vitro evidence demonstrating that porc is involved specifically in the processing of Wg. We identified a human sequence related to Porc suggesting the existence of a family of proteins involved in processing of Wnts.

Amino Acid Sequence↗

PubMed1996

Analysis of the pancreatic beta cell in the mouse with targeted disruption of the pancreatic beta cell-specific glucokinase gene.

This is the first systematic study on the pancreatic beta cell function in the heterozygous mouse with targeted disruption of the beta cell glucokinase gene. The heterozygotes' beta cell displayed the following characteristics: (1) impaired glucose sensitivity with normal glucose responsiveness, (2) poor discrimination of alpha and beta glucose anomers, and (3) normal response to glucose in the presence of 25 mM K+ and 150 microM diazoxide. Both the first and the second phases of glucose-stimulated insulin release were depressed. Although the heterozygotes were mildly hyperglycemic, insulin treatment further suppressed beta cell function, implying the beta cell glucose toxicity is not the cause of impaired glucose sensitivity. The data are compatible with the glucokinase glucose sensor concept inasmuch as glucose sensitivity is reduced in the heterozygotes' beta cell. The anomeric malaise and preservation of the ATP-sensitive K+ channel-independent glucose action were considered due to chronic hyperglycemia.

Animals↗

PubMed1996

Annexin II is a novel player in insulin signal transduction. Possible association between annexin II phosphorylation and insulin receptor internalization.

Annexin II is a Ca2+-, phospholipid-, and actin- binding protein that was implicated in the regulation of vesicular traffic and endosome fusion. It is a known substrate for protein kinases including the platelet-derived growth factor receptor, src protein-tyrosine kinase, and protein kinase C. In the present study we investigated the possible involvement of annexin II in insulin signal transduction. Phosphorylation of annexin II in response to insulin treatment of intact Chinese hamster ovary (CHO)-T cells was detected by 5 min and reached maximal levels after a 2-3-h incubation with the hormone. However, unlike other receptor substrates, annexin II failed to undergo insulin-induced Tyr phosphorylation under conditions where receptor internalization was inhibited. This was evident in CHO cells, overexpressing the insulin receptor, in which internalization was inhibited either by tyrosine kinase inhibitors or by lowering the temperature to 4 degrees C, and in CHO cells overexpressing various insulin receptor mutants in which normal internalization was impaired. Hence, Tyr phosphorylation of annexin II could be part of the internalization and sorting mechanism of the insulin receptor.

Androstadienes↗

PubMed1996

Mutant of insulin receptor substrate-1 incapable of activating phosphatidylinositol 3-kinase did not mediate insulin-stimulated maturation of Xenopus laevis oocytes.

Insulin receptor substrate-1 (IRS-1) is rapidly phosphorylated on multiple tyrosine residues in response to insulin and binds several Src homology 2 domain-containing proteins, thereby initiating downstream signaling. To assess the tyrosine phosphorylation sites that mediate relevant downstream signaling and biological effects, we created site-directed mutants of IRS-1 and overexpressed them in the Xenopus laevis oocyte. In oocytes overexpressing IRS-1 or IRS-1-895F (Tyr-895 replaced with phenylalanine), insulin activated phosphatidylinositol (PI) 3-kinase, p70 S6 kinase, and mitogen-activated protein kinase and induced oocyte maturation. In contrast, in oocytes overexpressing IRS-1-4F (Tyr-460, Tyr-608, Tyr-939, and Tyr-987 of IRS-1 replaced with phenylalanine), insulin did not activate PI 3-kinase, p70 S6 kinase, and mitogen-activated protein kinase and failed to induce oocyte maturation. These observations indicate that in X. laevis oocytes overexpressing IRS-1, the association of PI 3-kinase rather than Grb2 (growth factor-bound protein 2) with IRS-1 plays a major role in insulin-induced oocyte maturation. Activation of PI 3-kinase may lie upstream of mitogen-activated protein kinase activation and p70 S6 kinase activation in response to insulin.

Adaptor Proteins, Signal Transducing↗

PubMed1996

Hypoxia and hypoxia/reoxygenation activate Src family tyrosine kinases and p21ras in cultured rat cardiac myocytes.

We previously reported that both hypoxia and hypoxia followed by reoxygenation (hypoxia/reoxygenation) rapidly and sequentially activate mitogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-1. This was followed by the sequential activation of MAP kinase kinase (MAPKK). MAP kinases (p42mopk and p44mopk), and S6 kinase (p90rsk). In this study, we demonstrated that both hypoxia and hypoxia/ reoxygenation caused rapid activation of Src family tyrosine kinases, p60c-src and p59c-fyn, which are upstream mediators of MAP kinase activation. This was followed by the activation of p21ras. Because Src family tyrosine kinases are known to be cell-surface-associated kinases and upstream regulators of p21ras, these results strongly suggested that activation of Src family tyrosine kinases plays a key role in triggering intracellular signaling cascades in cardiac myocytes in response to hypoxia and hypoxia/reoxygenation.

Animals↗

PubMed1996

A large DNA-binding nuclear protein with RNA recognition motif and serine/arginine-rich domain.

cDNA species encoding a large DNA-binding protein (NP220) of 1978 amino acids was isolated from human cDNA libraries. Human NP220 binds to double-stranded DNA fragments by recognizing clusters of cytidines. Immunofluorescent microscopy with antiserum directed against NP220 revealed a punctate or "speckled" pattern and coiled body-like structures in the nucleoplasm of various human cell lines. These structures diffused in the cytoplasm during mitosis. Western blot analysis showed that NP220 is enriched in the lithium 3,5-diiodosalicylate-insoluble fraction of nuclei. The domain essential for DNA binding is localized in C-terminal half of NP220. Human NP220 shares three types of domains (MH1, MH2, and MH3) with the acidic nuclear protein, matrin 3 (Belgrader, P., Dey, R., and Berezney, R. (1991) J. Biol. Chem. 266, 9893-9899). MH1 is a 48-amino acid sequence near the N terminus of both human NP220 and rat matrin 3. MH2 is a 75-amino acid sequence homologous to the RNA recognition motifs of heterogeneous nuclear RNP I and L. It is repeated three times in NP220 and twice in matrin 3. MH3 is a 60-amino acid sequence at the C terminus of both NP220 and matrin 3. NP220 has an arginine/serine-rich domain commonly found in pre-mRNA splicing factors. Close to the domain essential for DNA binding, there are nine repeats of the sequence LVTVDEVIEEEDL. Thus, NP220 is a novel type of nucleoplasmic protein with multiple domains.

Amino Acid Sequence↗

PubMed1996

[Mitochondria gene mutation and diabetes].

Explore the source record for details and available documents.

Diabetes Mellitus↗

PubMed1996

Decreased E-cadherin expression is associated with haematogenous recurrence and poor prognosis in patients with squamous cell carcinoma of the oesophagus.

Reduced expression of E-cadherin is associated with tumour invasiveness and metastasis. To elucidate whether E-cadherin expression correlates with clinical outcome in patients with oesophageal cancer, 62 patients were investigated immunohistochemically using an anti-E-cadherin monoclonal antibody (HECD-1). Eight patients had normal levels of expression in the tumour, 25 had tumours that expressed high levels (50 per cent or more tumour cells staining positive for E-cadherin) and 29 had tumours expressing low levels (less than 50 per cent of cells expressing E-cadherin). Patients with normally expressing tumours had a better prognosis at 3 years than those with low-expressing tumours (P < 0.05). Postoperative death was correlated significantly with lymphatic invasion, lymph node metastasis, E-cadherin expression and depth of invasion (P < 0.05). Furthermore, haematogenous recurrence was correlated with E-cadherin expression (rs = 0.38, P < 0.01) and blood vessel invasion (rs = 0.28, P < 0.05). These results suggest that evaluation of E-cadherin immunoreactivity may predict haematogenous recurrence and poor prognosis in patients with oesophageal cancer.

Adult↗

PubMed1996

Structure and function of a novel arginine-specific cysteine proteinase (argingipain) as a major periodontal pathogenic factor from porphyromonas gingivalis.

Explore the source record for details and available documents.

Adhesins, Bacterial↗

PubMed1996

Maternally inherited diabetes and deafness: a new diabetes subtype.

Diabetes mellitus is a common disease with many forms of clinical expression. In addition, the development of diabetic complications is not only dependent on glycaemic control but also on individual factors which may be related to genetic heterogeneity. At present, multiple genetic factors are being recognized as contributing to the development of diabetes or possibly modulating its clinical expression. The purpose of this review is to give an overview of our current knowledge on a subtype of diabetes which is apparently caused by a single mutation in the mitochondrial DNA.

Base Sequence↗

PubMed1996

Problems in the health management of persons with spinal cord injury.

This study was conducted to clarify the features of complications attending spinal cord injury (SCI). A comparison was made of the prevalence of disease among patients with SCI (SCIP) with that in the general population in Japan (National Livelihood Basic Survey). For this purpose, a survey was conducted on 244 males at 8 Rosai Rehabilitation Centers (Workman's Accident Compensation Rehabilitation Workshops). The average age was 49.6 years. To eliminate age effects on this parameter, the prevalence rates were expressed as standardized outpatient morbidity ratios (SOMRs), with the value for the general population set at 100. The SOMR data for cystitis were particularly high (16,278, p < 0.01). The SOMRs for other diseases were also high: renal diseases, 2,642; disorders of the skin, 361; gastritis, 339; and hepatic disorders, 381 (p < 0.01). These disorders may be regarded as primary or secondary lesions associated with SCI. SCIP with diseases associated with aging, such as hypertension and diabetes mellitus, are on the increase in Japan. The SOMR for hypertension was 250 (p < 0.01), and for diabetes mellitus it was 323 (p < 0.01).

Adult↗

PubMed1996

The molecular basis and clinical characteristics of Maternally Inherited Diabetes and Deafness (MIDD), a recently recognized diabetic subtype.

Diabetes mellitus comprises a number of diseases with hyperglycemia as hallmark. Currently, multiple genetic factors are being recognized which contribute to the development of diabetes or which may modulate its clinical expression. This review presents an overview of our current knowledge on a diabetic subtype which associates with a single mutation in mitochondrial DNA. Based on the triad of Maternal Inheritance, Diabetes and Deafness we propose the name Maternally Inherited Diabetes and Deafness (MIDD) for this syndrome. In Northwestern Europe MIDD affects approximately 1.3% of all diabetic individuals.

Adult↗