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Gang Liu

Publications and source records attributed to Gang Liu.

At least 181 records · Page 10Linked to original sources
PubMed2003

Identification of a monoacid-based, cell permeable, selective inhibitor of protein tyrosine phosphatase 1B.

Monoacid-based PTP1B inhibitors with improved physiochemical properties have been investigated. A (2-hydroxy-phenoxy) acetic acid-based phosphotyrosyl mimetic has been linked with an optimized second arylphosphate binding site ligand to produce compound 20 with low micromolar potency against PTP1B, good selectivity over TCPTP (20-fold) and high cell permeability in the Caco-2 system.

Catalytic Domain↗
PubMed2003

bri3, a novel gene, participates in tumor necrosis factor-alpha-induced cell death.

bri3 was identified to be a novel gene up-regulated in TNF-treated cells with suppressed subtractive hybridization (SSH) in our laboratory. Previous studies showed that overexpression of BRI3 induced apoptosis in L929 cells. To further study the function of bri3, we disrupted its expression by expressing bri3 antisense RNA. The antisense RNA promoted resistance to TNF-induced cell death by more than 1000-fold in L929 cells, suggesting the involvement of BRI3 in TNF-induced cell death in this cell line. Analysis of cell death caused by other apoptotic inducers showed that the effect of BRI3 antisense RNA is highly specific to TNF-induced cell death. Taken together, bri3 appears to play an important role in TNF-induced cell death. Finally, we reported here that BRI3 may be localized to lysosome and function through lysosome.

Animals↗
PubMed2003

Specific oligobodies against human brain acetylcholinesterase.

In order to develop the specific oligobodies against human brain acetylcholinesterase (AChE) and distinguishes between human erythrocyte and brain AChEs, we applied the strategy of 'target switching' to obtain the specific polyclonal and monoclonal oligobodies. The specificity between human brain AChE and other ChEs was identified by Western blotting, dot blotting and enzyme protein binding assay (EPBA). The results showed that the oligobodies against the human brain AChE specifically immunoreacted with the human brain AChE and Torpedo AChE, not showing significant binding to AChE from human erythrocyte and butyrylcholinesterase (BChE) from human serum.

Acetylcholinesterase↗
PubMed2003

Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAbeta knockout NOD mice.

A line of nonobese diabetic (NOD) mice expressing the human diabetes-associated HLA-DQ8 transgene in the absence of mouse IAbeta failed to show spontaneous insulitis or diabetes, but rather developed dilated cardiomyopathy, leading to early death from heart failure. Pathology in these animals results from an organ- and cell-specific autoimmune response against normal cardiomyoctes in the atrial and ventricular walls, as well as against very similar myocytes present in the outermost muscle layer surrounding the pulmonary veins. Progression of the autoimmune process could be followed by serial ECG measurements; irradiation of young animals significantly delayed disease progression, and this effect could be reversed by adoptive transfer of splenocytes taken from older animals with complete heart block. Disease progression could also be blocked by cyclosporin A treatment, but was accelerated by injection of complete Fruend's adjuvant. The constellation of findings of spontaneously arising destructive focal lymphocytic infiltrates within the myocardium, rising titers of circulating anticardiac autoantibodies, dilation of the cardiac chambers, and gradual progression to end-stage heart failure bears a striking resemblance to what is seen in humans with idiopathic dilated cardiomyopathy, a serious and often life-threatening medical condition. This transgenic strain provides a highly relevant animal model for human autoimmune myocarditis and postinflammatory dilated cardiomyopathy.

Animals↗
PubMed2003

Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor.

Using an NMR-based fragment screening and X-ray crystal structure-based assembly, starting with millimolar ligands for both the catalytic site and the second phosphotyrosine binding site, we have identified a small-molecule inhibitor of protein tyrosine phosphatase 1B with low micromolar inhibition constant, high selectivity (30-fold) over the highly homologous T-cell protein tyrosine phosphatase, and good cellular activity in COS-7 cells.

Animals↗
PubMed2003

Selective protein tyrosine phosphatase 1B inhibitors: targeting the second phosphotyrosine binding site with non-carboxylic acid-containing ligands.

Protein tyrosine phosphatase (PTPase) 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling cascades. We identified several salicylic acid-based ligands for the second phosphotyrosine binding site of PTP1B using a NMR-based screening. Structure-based linking with a catalytic site-directed oxalylarylaminobenzoic acid-based pharmacophore led to the identification of a novel series of potent PTP1B inhibitors exhibiting 6-fold selectivity over the highly homologous T-cell PTPase (TCPTP) and high selectivity over other phosphatases.

Catalytic Domain↗
PubMed2003

Characterization of p73 functional domains necessary for transactivation and growth suppression.

p73, a p53 family member, is highly similar to p53 in both structure and function. Like p53, the p73 protein contains an N-terminal activation domain, a DNA-binding domain, a tetramerization domain, and several PXXP motifs. Previously, we and others have shown that some functional domains in p53, such as the DNA-binding and tetramerization domains, are required for inducing both cell cycle arrest and apoptosis whereas others, such as the second activation domain, the proline-rich domain, and the C-terminal basic domain, are only required for inducing apoptosis. To determine the activity of p73 functional domains, we have generated stable inducible cell lines that express p73beta and various mutants deficient in one or more functional domains. We found that in addition to the DNA-binding domain, p73-mediated growth suppression requires the N-terminal activation domain and the tetramerization domain. However, unlike p53, p73-mediated apoptosis does not require the region adjacent to the activation domain or the entire C-terminal region. Interestingly, while the N- or the C-terminal PXXP motifs are dispensable for p73 function, deletion of both the N- and the C-terminal PXXP motifs renders p73 inactive in transactivation. In addition, we found that substitution of two conserved tandem hydrophobic residues with two hydrophilic ones, which can abrogate the activity of the first activation domain in p53, has no effect on p73 transcriptional activity. Together, we showed that the p73 protein has its own unique determinants for transactivation and growth suppression.

Amino Acid Motifs↗
PubMed2003

Molecular level study of the formation and the spread of MoO3 on Au(111) by scanning tunneling microscopy and X-ray photoelectron spectroscopy.

The formation of MoO(3) and its spontaneous spread over an Au (111) surface have been studied by X-ray photoelectron spectroscopy (XPS) and scanning tunneling microscopy (STM). Metallic Mo clusters grown by Mo(CO)(6) chemical vapor deposition (CVD) have a constant size independent of the Mo coverage. Molecular oxygen does not react with low coverage of Mo, probably due to the encapsulation of the Mo clusters by Au. At higher coverage, O(2) reacts with Mo, partially transforming the metallic Mo to Mo(4+). NO(2) can oxidize Mo efficiently to Mo(6+) and Mo(5+) species at all coverages investigated. XPS experiments show that the integrated intensity of the Mo 3d peaks increases by a factor of 2 upon the oxidation, suggesting the spread of the MoO(3) over the surface. The STM study confirms this suggestion and provides the mechanistic details of the spreading. Mo oxide forms ramified two-dimensional islands covering a substantially larger fraction of the Au surface than the metallic Mo. We propose that the morphology change starts with the diffusion of oxide clusters (ramified-cluster-diffusion mechanism), followed by their breakdown to highly disordered two-dimensional islands of molecular MoO(3).

Journal Article↗
PubMed2003

Potent, selective inhibitors of protein tyrosine phosphatase 1B.

We have previously reported a novel series of oxalyl-aryl-amino benzoic acid-based, catalytic site-directed, competitive, reversible protein tyrosine phosphatase 1B (PTP1B) inhibitors. With readily access to key intermediates, we utilized a solution phase parallel synthesis approach and rapidly identified a highly potent PTP1B inhibitor (19, K(i)=76 nM) with moderate selectivity (5-fold) over T-cell PTPase (TCPTP) through interacting with a second phosphotyrosine binding site (site 2) in the close proximity to the catalytic site.

Amides↗
PubMed2003

Discovery and structure-activity relationship of oxalylarylaminobenzoic acids as inhibitors of protein tyrosine phosphatase 1B.

Protein Tyrosine phosphatase 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling pathways. Using an NMR-based screening approach with 15N- and 13C-labeled PTP1B, we have identified 2,3-dimethylphenyloxalylaminobenzoic acid (1) as a general, reversible, and competitive PTPase inhibitor. Structure-based approach guided by X-ray crystallography facilitated the development of 1 into a novel series of potent and selective PTP1B inhibitors occupying both the catalytic site and a portion of the noncatalytic, second phosphotyrosine binding site. Interestingly, oral biovailability has been observed in rats for some compounds. Furthermore, we demonstrated in vivo plasma glucose lowering effects with compound 12d in ob/ob mice.

4-Aminobenzoic Acid↗
PubMed2003

Apoptosis genes in human alveolar macrophages infected with virulent or attenuated Mycobacterium tuberculosis: a pivotal role for tumor necrosis factor.

Tumor necrosis factor (TNF)-alpha-dependent apoptosis of alveolar macrophages (AM) after infection with avirulent Mycobacterium tuberculosis (Mtb) results in bacillary death and the destruction of a growth niche for the pathogen. This response is minimized after infection with virulent strains of Mtb. To study the genetic control of Mtb-induced apoptosis, we used microarrays to interrogate the expression profile of infected human AM. Although we found variation in gene expression between different donors of AM, a set of genes were constant for each condition. A group of proapoptotic genes were downregulated after infection by virulent Mtb strain H37Rv, whereas infection with avirulent Mtb H37Ra led to a gene expression profile that would favor macrophage apoptosis. Neutralizing TNF in macrophage cultures infected with H37Ra changed the gene expression profile to one that resembled the profile of macrophages infected with H37Rv. These data reveal that apoptosis-related genes are regulated differently by virulent or attenuated Mtb strains, and are consistent with the hypothesis that virulent Mtb interfere with TNF death signaling. Given the importance of TNF in host defense against tuberculosis, the ability to repress the expression of genes activated by TNF may constitute a bacillary virulence mechanism.

Apoptosis↗
PubMed2003

[Transanal pull-through for Hirschsprung disease in new borns and infants].

OBJECTIVE: To introduce the transanal pull-through for congenital Hirschsprung's disease in new borns and infants. METHODS: The 43 cases on whom were performed transanal pull-through for Hirschsprung's disease were reviewed. The ages of the patients were 14 days-12 months. The technique included a rectal mucosectomy at the proximal to the dentate line, separating mucosas from rectal wall to the peritoneal reflection. The part of rectal muscularis below the peritoneal was resected posteriorly. An anastomosis was made between the pull-through ganglionic colon and anus. RESULTS: In the 43 cases the operations were easily accomplished by excising the injured intestine. The blood lost was small. The patients took food after 1-2 days of operation. discharged 5-7 days later. No retention of urine and no infection of incision wound were observed. Total follow up lasted 3-9 months. Defecation was normal, and there was no stricture of anus. Only 2 cases had soiling by chance. CONCLUSION: Simple transanal pull-through is an ideal type of operation for congenital Hirschsprung's disease in new borns and infants. It is an easy operation, with less injury, quick recovery and rare complication.

Anal Canal↗
PubMed2003

[Effects of collagen I coating on the porous poly-lactide-co-glycolid on adhesion, proliferation, and differentiation of mesenchymal stem cells].

OBJECTIVE: To investigate the effects of collagen I on the adhesion, proliferation, and differentiation of MSCs on PLGA. METHODS: Collagen I was added onto the surface of pores in pieces of 3-D porous poly-lactide-co-glycolid (PLGA). Bone marrow-derived mesenchymal stem cells (MSCs) were obtained from New Zealand rabbits and were cultured for 3 generations, inoculated into the pores of PLGA pieces with the volume of 0.3 cm x 1.2 cm x 2.0 cm, and then cultured in solution with [(3)H]-thymidine deoxyribose (TdR). PLGA pieces not coated by collagen I were used as controls. The incorporation rate of [(3)H]-TdR was detected 2, 4, 6, and 8 hours, and 7, 14, and 21 days after culture, shown in count per minute (CPM) value, to determine the adhesion and proliferation of the MSCs. RT-POCR was used to examine the expressions of mRNA of the osteoblast markers: osteocalcin (OCN), alkaline phosphatase (ALP), and osteopontin (OPN). Scanning electron microscopy (SEM) was used to observe the morphology of MSCs. RESULTS: The CPM value since 6 hours after culture between the experimental group and control group began to be significantly different (both P < 0.05) The CPM values 7, 14, and 21 days after culture between the experimental group and control groups (P < 0.05 or P < 0.01). OCN, ALP, and OPN mRNA were expressed in MSCs of the experimental group and only ALP mRNA was weakly expressed in the control group. SEM showed the distribution of spindle and polygonal cells in the pores of the 3-D PLGA pieces and distribution of cylindrical or round cells in the control group. CONCLUSION: Collagen I is effective in promoting the adhesion, proliferation, and differentiation of MSCs on PLGA.

Animals↗
PubMed2003

Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy.

Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. In this work, NMR-based screening identified a nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-based screening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and good selectivity over many other phosphatases. The modular approach to drug design described in this work should be applicable for the design of potent and selective inhibitors of other therapeutically relevant protein tyrosine phosphatases.

Amino Acid Sequence↗
PubMed2003

The activation domains, the proline-rich domain, and the C-terminal basic domain in p53 are necessary for acetylation of histones on the proximal p21 promoter and interaction with p300/CREB-binding protein.

The p53 transcription factor contains two separate tandem activation domains (AD1 and AD2), a proline-rich domain (PRD), and a C-terminal basic domain (BD). Previously, we have shown that these domains are necessary for transcriptional activity. To further characterize the role of these domains in transactivation, we analyzed the regulation of p21, a well characterized p53 target gene, by various p53 mutants deficient in one or more of these domains. We found that the induction of endogenous p21 is compromised by AD1-deficient p53 (p53(AD1(-))), AD2-deficient p53 (p53(AD2(-))), both AD1- and AD2-deficient p53 (p53(AD1(-)AD2(-))), p53(deltaPRD), which lacks PRD, and p53(deltaBD), which lacks BD. However, p53(AD2(-)), p53(deltaPRD), and p53(deltaBD) are still capable of activating exogenous p21 promoter to an extent comparable with that by wild-type p53. Thus, we performed chromatin immunoprecipitation assay to measure the DNA binding ability of various p53 mutants in vivo. We found that like wild-type p53, these p53 mutants are capable of binding to the p53 response elements in the p21 promoter. In contrast, we found that the extent of acetylated histones on the p21 promoter, especially the proximal promoter, and the amount of interaction with p300/CREB-binding protein, which contain histone acetyltransferase activity, directly correlate with the activity of p53 to induce endogenous p21. Furthermore, we showed that down-regulation of p300/CBP by short interference RNA markedly decreases the ability of p53 to induce endogenous p21. These data lead us to hypothesize that when p53 binds to the responsive element(s) of a target gene, its ability to interact with histone acetyltransferase-containing proteins and subsequently the acetylation of histones bound to the proximal promoter dictate the induction level of a target gene.

Acetylation↗
PubMed2003

The interaction between ADAM 22 and 14-3-3zeta: regulation of cell adhesion and spreading.

The ADAM family consists of a number of transmembrane proteins that contain disintegrin-like and metalloproteinase-like domains. Therefore, ADAMs potentially have cell adhesion and protease activities. 14-3-3 proteins are a highly conserved family of cytoplasmic proteins that associate with several intracellular signaling molecules in the regulation of various cellular functions. Here we report the identification of a novel interaction between the ADAM 22 cytoplasmic tail and the 14-3-3zeta isoform by a yeast two-hybrid screen. The interaction between the ADAM 22 cytoplasmic tail and 14-3-3zeta was confirmed by an in vitro protein pull-down assay as well as by co-immunoprecipitation, and the binding sites were mapped to the 28 amino acid residues of the C-terminus of the ADAM 22 cytoplasmic tail. Furthermore, we found that overexpression of the ADAM 22 cytoplasmic tail in human SGH44 cells inhibited cell adhesion and spreading and that deletion or mutation of the binding site for 14-3-3zeta within the ADAM 22 cytoplasmic tail abolished the ability of the overexpressed cytoplasmic tail to alter cell adhesion and spreading. Taken together, these results for the first time demonstrate an association between ADAM 22 and a 14-3-3 protein and suggest a potential role for the 14-3-3zeta/ADAM 22 association in the regulation of cell adhesion and related signaling events.

14-3-3 Proteins↗