Biomedical subjects

Hua Deng

Publications and source records attributed to Hua Deng.

At least 19 recordsLinked to original sources

PubMed2024

Hyd/UBR5 defines a tumor suppressor pathway that links Polycomb repressive complex to regulated protein degradation in tissue growth control and tumorigenesis.

Tumor suppressor genes play critical roles in normal tissue homeostasis, and their dysregulation underlies human diseases including cancer. Besides human genetics, model organisms such as Drosophila have been instrumental in discovering tumor suppressor pathways that were subsequently shown to be highly relevant in human cancer. Here we show that hyperplastic disc (Hyd), one of the first tumor suppressors isolated genetically in Drosophila and encoding an E3 ubiquitin ligase with hitherto unknown substrates, and Lines (Lin), best known for its role in embryonic segmentation, define an obligatory tumor suppressor protein complex (Hyd-Lin) that targets the zinc finger-containing oncoprotein Bowl for ubiquitin-mediated degradation, with Lin functioning as a substrate adaptor to recruit Bowl to Hyd for ubiquitination. Interestingly, the activity of the Hyd-Lin complex is directly inhibited by a micropeptide encoded by another zinc finger gene, drumstick (drm), which functions as a pseudosubstrate by displacing Bowl from the Hyd-Lin complex, thus stabilizing Bowl. We further identify the epigenetic regulator Polycomb repressive complex1 (PRC1) as a critical upstream regulator of the Hyd-Lin-Bowl pathway by directly repressing the transcription of the micropeptide drm Consistent with these molecular studies, we show that genetic inactivation of Hyd, Lin, or PRC1 resulted in Bowl-dependent hyperplastic tissue overgrowth in vivo. We also provide evidence that the mammalian homologs of Hyd (UBR5, known to be recurrently dysregulated in various human cancers), Lin (LINS1), and Bowl (OSR1/2) constitute an analogous protein degradation pathway in human cells, and that OSR2 promotes prostate cancer tumorigenesis. Altogether, these findings define a previously unrecognized tumor suppressor pathway that links epigenetic program to regulated protein degradation in tissue growth control and tumorigenesis.

Animals↗

PubMed2007

Inhibition and structure of Trichomonas vaginalis purine nucleoside phosphorylase with picomolar transition state analogues.

Trichomonas vaginalis is a parasitic protozoan purine auxotroph possessing a unique purine salvage pathway consisting of a bacterial type purine nucleoside phosphorylase (PNP) and a purine nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition state mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a Km/Kd ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a Km/Kd ratio of 203,300. The tight binding of DADMe-ImmA supports a late SN1 transition state. Despite their tight binding to TvPNP, ImmA and DADMe-ImmA are weak inhibitors of human and P. falciparum PNPs. The crystal structures of the TvPNP x ImmA x PO4 and TvPNP x DADMe-ImmA x PO4 ternary complexes differ from previous structures with substrate analogues. The tight binding with DADMe-ImmA is in part due to a 2.7 A ionic interaction between a PO4 oxygen and the N1' cation of the hydroxypyrrolidine and is weaker in the TvPNP x ImmA x PO4 structure at 3.5 A. However, the TvPNP x ImmA x PO4 structure includes hydrogen bonds between the 2'-hydroxyl and the protein that are not present in TvPNP x DADMe-ImmA x PO4. These structures explain why DADMe-ImmA binds tighter than ImmA. Immucillin-H is a 12 nM inhibitor of TvPNP but a 56 pM inhibitor of human PNP. And this difference is explained by isotope-edited difference infrared spectroscopy with [6-18O]ImmH to establish that O6 is the keto tautomer in TvPNP x ImmH x PO4, causing an unfavorable leaving-group interaction.

Adenine↗

PubMed2006

Phosphate activation in the ground state of purine nucleoside phosphorylase.

Phosphate and ribose 1-phosphate (R1P) bound to human purine nucleoside phosphorylase (PNP) have been studied by FTIR spectroscopy for comparison with phosphate bound with a transition state analogue. Bound phosphate is dianionic but exists in two distinct binding modes with similar binding affinities. The phosphate of bound R1P is also dianionic. Bound R1P slowly hydrolyzes to ribose and phosphate even in the absence of nucleobase. The C-OP bond is cleaved in bound R1P, the same as in the PNP-catalyzed reaction. Free R1P undergoes both C-OP and CO-P solvolysis. A hydrogen bond to one P-O group is stronger than those to the other two P-O groups in both the PNP.R1P complex and in one form of the PNP.PO4 complex. The average hydrogen bond strength to the PO bonds in the PNP.R1P complex is less than that in water but stronger than that in the PNP.PO4 complex. Hydrolysis of bound R1P may be initiated by distortion of the phosphate moiety in bound R1P. The unfavorable interactions on the phosphate moiety of bound R1P are relieved by dissociation of R1P from PNP or by hydrolysis to ribose and phosphate. The two forms of bound phosphate in the PNP.PO4 complex are interpreted to be phosphate positioned as the product in the nucleoside synthesis direction and as the reactant in the phosphorolysis reaction; their interconversion can occur by the transfer of a proton from one PO bond to another. The electronic structure of phosphate bound with a transition state analogue differs substantially from that in the Michaelis complexes.

Binding Sites↗

PubMed2006

On the new method for the control of discrete nonlinear dynamic systems using neural networks.

This correspondence points out an incorrect statement in Adetona et al, 2000, and Adetona et al., 2004, about the application of the proposed control law to nonminimum phase systems. A counterexample shows the limitations of the control law and, furthermore, its control capability to nonminimum phase systems is explained.

Algorithms↗

PubMed2006

An approximate internal model-based neural control for unknown nonlinear discrete processes.

An approximate internal model-based neural control (AIMNC) strategy is proposed for unknown nonaffine nonlinear discrete processes under disturbed environment. The proposed control strategy has some clear advantages in respect to existing neural internal model control methods. It can be used for open-loop unstable nonlinear processes or a class of systems with unstable zero dynamics. Based on a novel input-output approximation, the proposed neural control law can be derived directly and implemented straightforward for an unknown process. Only one neural network needs to be trained and control algorithm can be directly obtained from model identification without further training. The stability and robustness of a closed-loop system can be derived analytically. Extensive simulations demonstrate the superior performance of the proposed AIMNC strategy.

Algorithms↗

PubMed2006

[Study on the membrane protein conformational changes and mechanisms of myocardial cell irradiated by pulse microwave].

Micro-Fourier transform infrared spectroscopy (FTIR) technique was applied to study the membrane protein conformational and functional changes of myocardial cell irradiated by pulse microwave. The results show that pulse microwave could influence the membrane protein structure markedly. The stretching vibration of lipid--CH2--, lecithoid C=O, amide I and II region was decreased or displaced. The secondary structures of membrane protein were also changed by irradiation. The percentage of alpha-helix and beta-pleated sheet structure decreased remarkably, and the disordering of secondary membrane proteins increased. All the above changes are correlated with the irradiation dosage. The results indicated that the integrality of myocardial cell membrane was injured by pulse microwave, and the membrane fluidity and stability decreased. Multi-biochemically active structures were damaged. Then all the changes could make a biochemical foundation of pathologic effects, which included membrane function decline, cell morphological change, configuration injuring and apoptosis etc. This paper is from a new view of protein conformation to explore the molecular pathologic mechanism of the damage caused by pulse microwave irradiation.

Animals↗

PubMed2005

Matrix metalloproteinase 11 depletion inhibits cell proliferation in gastric cancer cells.

Our previous study has shown that matrix metalloproteinase 11 (MMP11) is highly expressed in tumor cell lines and primary tumor of gastric cancer (GC). In order to reveal the correlation between expression of MMP11 and biological features of GC cell, we have constructed the recombinant plasmids producing hairpin small interfering RNA (siRNA) to target MMP11 mRNA using a vector-based RNA interference technology. Stable transfection of recombinants into GC cell line BGC823 specifically depleted the mRNA and protein of MMP11 as demonstrated by RT-PCR and Western blotting analysis. The siRNA-treated cells exhibited significantly decreased growth ability compared with mock transfectants and parental BGC823 cells. Furthermore, colony formation of MMP11 deficient cells was dramatically inhibited in soft agar and tumorigenicity was reduced in nude mice, respectively. These results provide new insights into the function of MMP11 and suggest that MMP11 may play an important role in the control of cell proliferation and tumor development in GC.

Animals↗

PubMed2005

A novel neural approximate inverse control for unknown nonlinear discrete dynamical systems.

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Algorithms↗

PubMed2005

[The electroporation effects of high power pulse microwave and electromagnetic pulse irradiation on the membranes of cardiomyocyte cells and the mechanism therein involved].

Though there is ongoing public concern on potential hazards and risk of electromagnetic radiation, the bioeffects mechanism of electromagnetic fields remains obscure. Heart is one of the organs susceptive to electromagnetic fields (EMF). This study was designed to assess the influence of high power pulse microwave and electromagnetic pulse irradiation on cardiomyocytes, to explore the critical mechanism of electromagnetic fields, and to explain the regular course of injury caused by exposure to pulse EMF. Cultured cardiomyocytes were irradiated by high power pulse microwave and electromagnetic pulse first, then a series of apparatus including atom force microscope, laser scanning confocal microscope and flow cytometer were used to examine the changes of cell membrane conformation, structure and function. After irradiation, the cardiomyocytes pulsated slower or stop, the cells conformation was abnormal, the cells viability declined, and the percentage of apoptosis and necrosis increased significantly (P< 0.01). The cell membrane had pores unequal in size, and lost its penetration character. The concentration of Na+, K+, Ca2+, Cl-, Mg2+, Ca2+ and P3+ in cell culture medium increased significantly (P< 0.01). and the concentration of Ca2+ in cells ([Ca2+]i) decreased significantly (P<0.01). The results indicated that cardiomyocytes are susceptible to non-ionizing radiation. Pulse electromagnetic field can induce cardiomyocytes electroporation, and can do great damage to cells conformation, structure and function. Electroporation is one of the most critical mechanisms to explain the athermal effects of electromagnetic radiation.

Animals↗

PubMed2004

Active site contacts in the purine nucleoside phosphorylase--hypoxanthine complex by NMR and ab initio calculations.

Hypoxanthine (Hx) with specific (15)N labels has been used to probe hydrogen-bonding interactions with purine nucleoside phosphorylase (PNP) by NMR spectroscopy. Hx binds to human PNP as the N-7H tautomer, and the N-7H (1)H and (15)N chemical shifts are located at 13.9 and 156.5 ppm, respectively, similar to the solution values. In contrast, the (1)H and (15)N chemical shifts of N-1H in the PNP.Hx complex are shifted downfield by 3.5 and 7.5 ppm to 15.9 and 178.8 ppm, respectively, upon binding. Thus, hydrogen bonding at N-1H is stronger than at N-7H in the complex. Ab initio chemical shift calculations on model systems that simulate Hx in solution and bound to PNP are used to interpret the NMR data. The experimental N-7H chemical shift changes are caused by competing effects of two active site contacts. Hydrogen bonding of Glu201 to N-1H causes upfield shifts of the N-7H group, while the local hydrogen bond (C=O to N-7H from Asn243) causes downfield shifts. The observed N-7H chemical shift can be reproduced by a hydrogen bond distance approximately 0.13 A shorter (but within experimental error) of the experimental value found in the X-ray crystal structure of the bovine PNP.Hx complex. The combined use of NMR and ab initio chemical shift computational analysis provides a novel approach to understand enzyme-ligand interactions in PNP, a target for anticancer agents. This approach has the potential to become a high-resolution tool for structural determination.

Animals↗

PubMed2004

Expanding amplitude-squeezing bandwidth with off-peak dispersive optical feedback.

Weak dispersive optical feedback has been proved both theoretically and experimentally to be able to reduce the intensity noise of semiconductor lasers and allow the generation of amplitude-squeezed states. I propose a novel scheme exploiting the off-peak optical feedback condition that expands the squeezing bandwidth and significantly enhances the repeatability over the most commonly utilized on-peak optical feedback scheme. Using a realistic model, I show that under the zero-frequency-pulling condition the off-peak scheme greatly enhances the squeezing bandwidth.

Journal Article↗

PubMed2004

Activating the phosphate nucleophile at the catalytic site of purine nucleoside phosphorylase: a vibrational spectroscopic study.

Difference Raman and FTIR studies complemented by vibrational analysis based on ab initio calculations show that the dianionic phosphate in the PNP.ImmH.PO4 complex is forced into a unique bonding arrangement in which one of the PO bonds is greatly polarized by enzyme active site interactions, such that it resembles a PO bond that is about one-quarter of the way toward forming a bridging P-O-C single P-O bond.

Animals↗

PubMed2004

The assignment of downfield proton resonances in an enzyme inhibitor complex using time-dependent saturation transferred NOEs.

We have used time-dependent saturation transferred NOE (STNOE) measurements to assign two downfield resonances in the proton spectrum of an adenosine deaminase-purine riboside mixture. Our results show that this method can be used to detect structural changes that occur upon inhibitor binding to the enzyme and to determine which protons of the bound inhibitor are strongly hydrogen bonded in the complex.

Adenosine Deaminase↗

PubMed2004

Assignment of downfield proton resonances in purine nucleoside phosphorylase immucillin-H complex by saturation-transferred NOEs.

Purine nucleoside phosphorylase (PNP) catalyzes N-ribosidic bond phosphorolysis in 6-oxypurine nucleosides and deoxynucleosides to form purine and alpha-D-phosphorylated ribosyl products. The transition state has oxacarbenium ion character with partial positive charge near C-1', ionic stabilization from the nearby phosphate anion, and protonation at N-7 of the purine. Immucillin-H (ImmH) has a protonated N-7 and resembles the transition-state charge distribution when N-4' is protonated to the cation. It binds tightly to the PNPs with a K(d) value 56 pM for human PNP. Previous NMR studies of PNP. ImmH.PO(4) have shown that the N-4' of bound ImmH is a cation and is postulated to have a significant contribution to its tight binding. Several unassigned downfield proton resonances (>11 ppm) are specific to the PNP. ImmH.PO(4) complex, suggesting the existence of strong hydrogen bonds. In this study, two of the proton resonances in this downfield region have been assigned. Using (15)N-7-labeled ImmH, a resonance at 12.5 ppm has been assigned to N-7H. The N-7H resonance is shifted downfield by only approximately 1 ppm from its position for ImmH free in aqueous solution, consistent with only a small change in the hydrogen bonding on N-7H upon binding of ImmH to PNP. In contrast, the downfield resonance at 14.9 ppm in the PNP. ImmH.PO(4) complex is assigned to N-1H of ImmH by using saturation-transferred NOE measurements on the PNP. ImmH complex. The approximately 4 ppm downfield shift of the N-1H resonance from its position for ImmH free in solution suggests that the hydrogen bonding to the N-1H in the complex has a significant contribution to the binding of ImmH to PNP. The crystal structure shows Glu201 is in a direct hydrogen bond with N-1H and to O-6 through a water bridge. In the complex with 6-thio-ImmH, the N-1H resonance is shifted further downfield by an additional 1.5 ppm to 16.4 ppm, but the relative shift from the value for 6-thio-ImmH free in solution is the same as in the ImmH complex. Since the binding affinity to hPNP for 6-thio-ImmH is decreased 440-fold relative to that for ImmH, the loss in binding energy is primarily due to the hydrogen bond energy loss at the 6-thiol.

Binding, Competitive↗

PubMed2004

Basic fibroblast growth factor inhibits radiation-induced apoptosis of HUVECs. I. The PI3K/AKT pathway and induction of phosphorylation of BAD.

Apoptosis↗

PubMed2004

Basic fibroblast growth factor inhibits radiation-induced apoptosis of HUVECs. II. The RAS/MAPK pathway and phosphorylation of BAD at serine 112.

Radiation-induced endothelial cell apoptosis is involved in the development of many radiation injuries, including radiation-induced skin ulcers. The proangiogenic growth factor basic fibroblast growth factor (bFGF, NUDT6) enhances endothelial cell survival. In the present study, we set up a model of apoptosis in which primary cultured human umbilical vein endothelial cells (HUVECs) were irradiated with (60)Co gamma rays to explore the effects of bFGF on radiation-induced apoptosis of HUVECs and the signaling pathways involved. We found that bFGF inhibited radiation-induced apoptosis of HUVECs, and that the effect was mediated in part by the RAS/MEK/ MAPK/RSK (p90 ribosomal S6 kinase)/BAD pathway. This pathway was activated by exposure of irradiated HUVECs to bFGF, involving phosphorylation of FGFR, MEK and p44/42 MAPK. The survival-enhancing effect of bFGF was partly inhibited by U0126 and PD98059. The fact that the anti-apoptosis effect of bFGF on irradiated HUVECs was not completely abrogated by U0126 and PD98059 suggests that other survival signaling pathways may exist. Transfection of a dominant-negative form of RSK2 (DN RSK2) partly blocked the anti-apoptosis effect of bFGF in irradiated HUVECs. Moreover, we provide evidence for the first time that bFGF induced BAD phosphorylation (at serine 112) and CREB (cAMP response element-binding protein) activation (phosphorylation at serine 133) in gamma-irradiated HUVECs. In our model, inhibition of MAPK signaling-dependent phosphorylation of BAD at serine 112 promoted increased association with BCL-X(L), suggesting that MAPK pathway-dependent serine 112 phosphorylation of BAD is critical for the effect of bFGF on cell survival. These results showed that RAS/MAPK/BAD pathway participated in the bFGF-induced effect on survival of HUVECs exposed to radiation. It is suggested that RAS/ MAPK pathway in tumor vascular endothelium could be a potential therapeutic target to enhance the efficacy of ionizing radiation.

Apoptosis↗

PubMed2003

PPARgamma pathway activation results in apoptosis and COX-2 inhibition in HepG2 cells.

AIM: To investigate whether troglitazone (TGZ), the peroxisome proliferator-activated receptor (PPAR) gamma ligand, can induce apoptosis and inhibit cell proliferation in human liver cancer cell line HepG2 and to explore the molecular mechanisms. METHODS: (3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), ((3)H) Thymidine incorporation, Hochest33258 staining, DNA ladder, enzyme-linked immunosorbent assay (ELISA), RT-PCR, Northern and Western blotting analyses were employed to investigate the effect of TGZ on HepG2 cells and related molecular mechanisms. RESULTS: TGZ was found to inhibit the growth of HepG2 cells and to induce apoptosis. During the process, the expression of COX-2 mRNA and protein and Bcl-2 protein was down-regulated, while that of Bax and Bak proteins was up-regulated, and the activity of caspase-3 was elevated. Furthermore, the level of PGE(2) was decreased transiently after 12 h of treatment with 30 microM troglitazone. CONCLUSION: TGZ inhibits cell proliferation and induces apoptosis in HepG2 cells, which may be associated with the activation of caspase-3-like proteases, down-regulation of the expression of COX-2 mRNA and protein, Bcl-2 protein, the elevation of PGE2 levels, and up-regulation of the expressions of Bax and Bak proteins.

Apoptosis↗

PubMed2003

Peroxisome proliferator-activated receptor gamma ligands inhibit cell growth and induce apoptosis in human liver cancer BEL-7402 cells.

AIM: To investigate the characteristics of PPAR gamma ligands induced apoptosis in liver cancer cells. METHODS: The effects of ligands for each of the PPAR gamma ligands on DNA synthesis and cell viability were examined in BEL-7402 liver cancer cells. Apoptosis was characterized by Hochest33258 staining, DNA fragmentation, TUNEL and ELISA, and cell cycle kinetics by FACS. Modulation of apoptosis related caspases expression by PPAR gamma ligands was examined by Western blot. RESULTS: PPARgamma ligands, 15-deoxy-(12), (14)-prostaglandin J2 (15d-PGJ2) and troglitazone (TGZ), suppressed DNA synthesis of BEL-7402 cells. Both 15d-PGJ2 and TGZ induced BEL-7402 cell death in a dose dependent manner, which was associated with an increase in fragmented DNA and TUNEL-positive cells. At concentrations of 10 and 30 microM, 15d-PGJ(2) or troglitazone increased the proportion of cells with G(0)/G(1) phase DNA content and decreased those with S phase DNA content. There was no significant change in the proportion of cells with G(2)/M DNA content. The activities of Caspases-3, -6, -7 and -9 were increased by 15d-PGJ2 and TGZ treatment, while the activity of Caspase 8 had not significantly changed. CONCLUSION: The present results suggest the potential usefulness of PPAR gamma ligands for chemoprevention and treatment of liver cancers.

Apoptosis↗