Glypican-3 induces oncogenicity by preventing IGF-1R degradation, a process that can be blocked by Grb10.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a major cause of cancer-related death worldwide. Previously, we demonstrated that glypican-3 (GPC3) is highly expressed in HCC, and that GPC3 induces oncogenicity and promotes the growth of cancer cells through IGF-1 receptor (IGF-1R). In the present study, we investigated the mechanisms of GPC3-mediated enhancement of IGF-1R signaling.

Gene therapy with modified U1 small nuclear RNA.

More than 15% of all disease-causing mutations result in mRNA splicing defects. U1 snRNA binds to the 5' splice site (5'ss) through base pairing. Mutation-adapted U1 snRNA (with compensatory U1 snRNA changes) and exon-specific U1 snRNA (complementary to intronic sequences) have been shown to suppress 5'ss mutations in cellular and animal models.

Mutation-adapted U1 snRNA corrects a splicing error of the dopa decarboxylase gene.

Aromatic l-amino acid decarboxylase (AADC) deficiency is an inborn error of monoamine neurotransmitter synthesis, which results in dopamine, serotonin, epinephrine and norepinephrine deficiencies. The DDC gene founder mutation IVS6 + 4A > T is highly prevalent in Chinese patients with AADC deficiency. In this study, we designed several U1 snRNA vectors to adapt U1 snRNA binding sequences of the mutated DDC gene.

The Novel VEGF121-VEGF165 Fusion Attenuates Angiogenesis and Drug Resistance via Targeting VEGFR2-HIF-1α-VEGF165/Lon Signaling Through PI3K-AKT-mTOR Pathway.

Anti-angiogenesis therapy is one major approach of cancer therapies nowadays. Unfortunately, anti-angiogenesis therapy targeting VEGF-A was recently stumbled by the drugresistance that results from adaptive mechanisms, such as intratumor hypoxia. To obtain a more efficient therapeutic response, we created and identified a novel chimeric fusion of VEGF121 and VEGF165, which was connected by Fc region of human IgG1 to enhance dimerization.

Exchange of active site residues alters substrate specificity in extremely thermostable β-glycosidase from Thermococcus kodakarensis KOD1.

β-Glycosidase from Thermococcus kodakarensis KOD1 is a hyperthermophilic enzyme with β-glucosidase, β-mannosidase, β-fucosidase and β-galactosidase activities. Sequence alignment with other β-glycosidases from hyperthermophilic archaea showed two unique active site residues, Gln77 and Asp206. These residues were represented by Arg and Asp in all other hyperthermophilic β-glycosidases.

An intermolecular disulfide bond is required for thermostability and thermoactivity of β-glycosidase from Thermococcus kodakarensis KOD1.

Scientists are interested in understanding the molecular origin of protein thermostability and thermoactivity for possible biotechnological applications. The enzymes from extremophilic organisms have been of particular interest in the last two decades. β-glycosidase, Tkβgly is a hyperthermophilic enzyme from Thermococcus kodakarensis KOD1.

Inhibition of glutaminyl cyclase attenuates cell migration modulated by monocyte chemoattractant proteins.

QC (glutaminyl cyclase) catalyses the formation of N-terminal pGlu (pyroglutamate) in peptides and proteins. pGlu formation in chemoattractants may participate in the regulation of macrophage activation and migration. However, a clear molecular mechanism for the regulation is lacking.

White spot syndrome virus protein ICP11: A histone-binding DNA mimic that disrupts nucleosome assembly.

White spot syndrome virus (WSSV) is a large ( approximately 300 kbp), double-stranded DNA eukaryotic virus that has caused serious disease in crustaceans worldwide. ICP11 is the most highly expressed WSSV nonstructural gene/protein, which strongly suggests its importance in WSSV infection; but until now, its function has remained obscure. We show here that ICP11 acts as a DNA mimic.

Glypican-3-mediated oncogenesis involves the Insulin-like growth factor-signaling pathway.

Glypican-3 (gpc3) is the gene responsible for Simpson-Golabi-Behmel overgrowth syndrome. Previously, we have shown that GPC3 is overexpressed in hepatocellular carcinoma (HCC). In this study, we demonstrated the mechanisms for GPC3-mediated oncogenesis.

Hsp27 decreases inclusion body formation from mutated GTP-cyclohydrolase I protein.

GTP cyclohydrolase I (GCH), an oligomeric protein composed of 10 identical subunits, is required for the synthesis of neurotransmitters; mutations in GCH are associated with dopa-responsive dystonia (DRD) and hyperphenylalaninemia. Mutated GCH proteins are unstable and prone to dominant-negative effect. We show herein that expression of the GCH mutant GCH-201E or the splicing variant GCH-II caused intracellular inclusion bodies.

Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington's disease patients.

Increased oxidative stress and mitochondrial abnormalities contribute to neuronal dysfunction in Huntington's disease (HD). We investigated whether these pathological changes in HD brains may also be present in peripheral tissues. Leukocyte 8-hydroxydeoxyguanosine (8-OHdG) and plasma malondialdehyde (MDA) were elevated, and activities of erythrocyte Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and glutathione peroxidase (GPx) reduced in 16 HD patients when compared to 36 age- and gender-matched controls.

Differential expression of mu-opioid receptor gene in CXBK and B6 mice by Sp1.

It is well known that there are individual differences in the sensitivity to analgesics. The CXBK mice are characterized by reduced sensitivity to morphine and by partial deficiency in mu-opioid receptor (MOR) expression. The sequences of MOR genes in CXBK and B6 mice are identical in their coding regions but differ at 5'-untranslated region (UTR) nucleotide -202 (C nucleotide in CXBK, but A nucleotide in B6).

RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter.

GTP cyclohydrolase I (GCH) is the rate-controlling enzyme in the production of tetrahydrobiopterin (BH4) that is essential for the synthesis of nitric oxide and catecholamines including dopamine and serotonin. Therefore, the regulation of GCH expression is important in determining the catecholamine levels in the brain under pathophysiological conditions. During the study of human disease dopa-responsive dystonia, we found that coactivator RNF4 is involved in the GCH gene expression.

Molecular chaperones affect GTP cyclohydrolase I mutations in dopa-responsive dystonia.

Unstable GTP cyclohydrolase I (GCH) mutations in dopa-responsive dystonia (DRD) can exert a dominant-negative effect in the HeLa cell model, but in a batch of cells this effect could not be shown. Through differential display, we found a higher Hsc70 expression in the non-dominant-negative cells. We further demonstrated that ectopic expression of Hsp40/Hsp70 stabilized the GCH mutant G201E.

Transcriptional regulation of mu opioid receptor gene by cAMP pathway.

The utility of morphine for the treatment of chronic pain is hindered by the development of tolerance. Fentanyl has been shown to be a potent analgesic with a lower propensity to produce tolerance and physical dependence in the clinical setting. Previous finding has shown that fentanyl induces mu opioid receptor gene expression in PC-12 cells (Brain Res 859:217-223, 2000).

Differential activation of a C/EBP beta isoform by a novel redox switch may confer the lipopolysaccharide-inducible expression of interleukin-6 gene.

C/EBP beta, a member of the CCAAT/enhancer binding protein (C/EBP) family, is one of the key transcription factors responsible for the induction of a wide array of genes, some of which play important roles in innate immunity, inflammatory response, adipocyte and myeloid cell differentiation, and the acute phase response. Three C/EBP beta isoforms (i.e.

Regulation of GTP cyclohydrolase I by alternative splicing in mononuclear cells.

GTP cyclohydrolase I (GCH, EC 3.5.4.