Biomedical subjects

H Yu

Publications and source records attributed to H Yu.

At least 109 records · Page 6Linked to original sources

PubMed2001

Meningeal carcinomatosis in patients with breast cancer: report of 8 patients.

BACKGROUND: Meningeal carcinomatosis (MC) is an uncommon but aggressive complication of advanced breast cancer with a recently increasing incidence. Although the prognosis is extremely poor for MC patients, early diagnosis and appropriate treatment are important. SUBJECTS AND METHODS: We reviewed 8 cases of MC from breast cancer at Kyoto University Hospital from 1990 to 1999. The median age was 51.5 years. All patients had widespread systemic metastases when diagnosed with MC. clinical symptoms were categorized into 3 groups: cranial nerve symptoms, spinal nerve symptoms, and other symptoms. Imaging studies were positive for MC in only 4 patients. Initial CSF cytology studies were positive in 4 patients, and repeated CSF cytology yielded positive results in the remaining 4 patients. Thus the median interval between the onset of any clinical symptom of MC and the initiation of treatment was 22.5 days (range 7 to 120 days ). All patients received whole brain radiotherapy (WBRT). Four patients were given intrathecal chemotherapy and/or intrathecal immunotherapy in addition to WBRT. RESULTS: Improvement of cranial nerve symptoms, spinal nerve symptoms, and other symptoms were observed in 3/5, 1/3, and 5/7 patients, respectively. Patients with cranial nerve symptoms who started WBRT within 29 days of the onset of the symptoms showed at least partial recovery whereas patients who started WBRT later showed no recovery. The median survival was 123 days (53 to 310 days). MC was the direct cause of death in 1 of 8 patients. CONCLUSION: When MC is clinically suspected, neither a negative imaging study nor a single negative CSF cytology can rule out MC. Prompt initiation of WBRT with or without intrathecal chemotherapy may be important for recovery from cranial nerve symptoms.

Adult↗

PubMed2001

Pharmacological characterisation of the decrease in 5-HT synthesis in the mouse brain evoked by the selective serotonin re-uptake inhibitor citalopram.

The selective serotonin re-uptake inhibitor (SSRI) citalopram decreases the synthesis of 5-hydroxytryptamine (5-HT) in the mouse brain in vivo. The underlying mechanism was studied by recording the accumulation of 5-hydroxytryptophan (5-HTP) in hypothalamus and hippocampus after inhibition of the aromatic amino acid decarboxylase activity with m-hydroxybenzylhydrazine (NSD 1015). Depletion of 5-HT with reserpine markedly reduced the citalopram-induced decrease of 5-HTP but not that evoked by the 5-HT1A receptor agonist 8-OH-DPAT, which indicates that the presence of endogenous 5-HT is necessary for full effect of citalopram. In contrast to the almost complete antagonism of the decrease in 5-HT synthesis induced by 8-OH-DPAT, the 5-HT1A receptor antagonist WAY-100,635 only slightly affected the citalopram-evoked decrease in 5-HT synthesis. Likewise, the 5-HT1B receptor antagonists NAS-181 and GR127935 only slightly antagonised the citalopram effect although they strongly inhibited the decrease in 5-HT synthesis induced by the 5-HT1B receptor agonist anpirtoline. Combined treatment with 5-HT1A and 5-HT1B receptor antagonists did not produce any additive antagonistic effect on the citalopram-induced decrease in 5-HT synthesis. The 5-HT2A/2C receptor antagonist ketanserin, the 5-HT3 receptor antagonist ondansetron and the 5-HT4 receptor antagonist RS-39604 had no effect on the citalopram-induced decrease in 5-HT synthesis. The same was found for several other non-selective 5-HT receptor antagonists, e.g. cyproheptadine, dihydroergotamine, methiothepin, methysergide, metergoline and mianserin. It is concluded that the citalopram-induced decrease in 5-HT synthesis differs in sensitivity from that mediated by 5-HT1A or 5-HT1B receptor agonists and citalopram also seems to require endogenous 5-HT for its full effect.

5-Hydroxytryptophan↗

PubMed2001

Development of the fragment constant method for estimating the partition coefficients of nonionic organic mixtures.

The fragment constant model for estimating partition coefficient of nonionic organic mixtures is developed based on group contribution theory. For 60 mixtures randomly composed of eight substituted benzenes, the C(18)-Empore disks/water partition coefficients (K(MD)) are determined. Establishment of a model between these K(MD) and the mole fraction of the fragments (Cl, Br, I, NO(2), CH(3)) acquires the fragments constants for K(MD). The significant linear regression equation, between these fragment constants and that of Hansch, provides an approach for calculating K(MD) of untested nonionic organic mixtures by using the fragment constants of Hansch.

Benzene↗

PubMed2001

The expression and regulation of depolarization-activated K+ channels in the insulin-secreting cell line INS-1.

The aim of the present study was to characterize depolarization-activated outward currents in insulin-secreting INS-1 cells and to investigate the role of K+ channels other than the KATP channels in the regulation of insulin release. Outward currents were inhibited by 4-aminopyridine (4-AP, 10 mmol/l), tetraethylammonium (TEA, 10 mmol/l) and tetrapentylammonium (TPeA, 100 mumol/l) by 55.1 +/- 3.8% (n = 3), 78.1 +/- 3.2% (n = 6) and 98.7 +/- 0.8% (n = 5), respectively. Margatoxin (5 nmol/l) and charybdotoxin (3 mumol/l) had no effect. 4-AP inhibited mainly a fast-activating, slowly inactivating current, whereas the TEA- and TPeA-sensitive current components were slowly activating and non-inactivating. Forskolin and the forskolin analogue 1,9-dideoxyforskolin, which does not stimulate adenylyl cyclase, also inhibited the outward current, suggesting a direct effect on the channels. Using reverse transcriptase polymerase chain reaction (RT/PCR). Kv channel mRNAs of Kv1.4, Kv1.5, Kv2.1, Kv2.2, Kv3.1 and Kv3.2 were detected whereas other Kv channels, Kv1.1, Kv1.2, Kv1.3, Kv1.6 and Kv3.4 were not detected. Insulin secretion in the presence of tolbutamide (100 mumol/l) was increased by 4-AP, TEA and TPeA by 65%, 41% and 150%, respectively. Basal secretion was not affected by these blockers. Our study reveals that the opening of voltage-dependent K+ channels negatively controls insulin secretion in depolarized cells, probably by shortening the action potential thus reducing Ca2+ influx.

1-Methyl-3-isobutylxanthine↗

PubMed2001

Vaccination with IL-18 gene-modified, superantigen-coated tumor cells elicits potent antitumor immune response.

OBJECTIVE: To investigate the induction of antitumor immune response by vaccination with interleukin-18 (IL-18) gene-modified, C215Fab-SEA-coated tumor cells. MATERIALS: A B16-C215 cell clone stably expressing C215 antigen was established by transfecting the gene-encoding C215 antigen into B16 melanoma cells. The manipulated tumor cell vaccine was prepared with B16-C215 cells genetically modified with the IL-18 gene, coated with the fusion protein of SEA and the Fab region of C215 mAb (C215Fab-SEA) which specifically binds to the C215 antigen and then irradiated. C57BL/6 mice were vaccinated with IL-18 gene-modified, C215Fab-SEA-coated B16-C215 cells followed by tumor challenge. Tumor growth and survival time were observed. The expansion of CD4+, CD8+ cells in lymphocytes derived from draining lymph node was detected by FACS. Induction of CTL activity by vaccination was measured by 51Cr release assay. RESULTS: IL-18 gene-modified, C215Fab-SEA-coated B16-C215 cell vaccine effectively stimulated lymphocyte proliferation and CD4+, CD8+ cell expansion in vitro. It was more immunogenic than B16-C215 cells genetically modified with IL-18 gene alone or B16-C215 cells coated with C215Fab-SEA alone. Immunization of the mice with the manipulated vaccine elicited protective immunity against the following tumor challenge of parental B16-C215 and wild-type B16 cells. Significant expansion of CD4+, CD8+ T cells was observed in the draining lymph node of the immunized mice when compared with that in unvaccinated mice. Higher CTL activity was induced in vaccinated mice than that in unvaccinated mice. CONCLUSION: Vaccination with IL-18 gene-modified, C215Fab-SEA-coated tumor cells elicited potent antitumor response through induction of tumor-specific immune response.

Animals↗

PubMed2001

T cell subsets and sIL-2R/IL-2 levels in patients with glaucoma.

PURPOSE: We hypothesize that cellular immunity may have a previously unrecognized role in glaucomatous optic neuropathy. The purpose of this study is to analyze subsets of T cells and the levels of cytokine IL-2 and the soluble IL-2 receptor in peripheral blood from patients with normal pressure glaucoma (NPG) or primary open angle glaucoma (POAG) in comparison to age-matched control subjects. METHODS: In this study, 38 patients (20 NPG; 18 POAG) and 19 controls were included. sIL-2R and IL-2 were assayed by ELISA. T cell subsets were analyzed by flow cytometry and lymphocyte proliferation was used to measure the reactive ability of T cells to phytohemagglutinin (PHA). RESULTS: The frequency of CD8(+)HLA-DR(+) lymphocytes were increased in patients with NPG (P = 0.008), and CD3(+)CD8(+) lymphocytes increased in both NPG (P = 0.03) and POAG patients (P = 0.0004). CD5(+) lymphocytes were higher only in POAG patients (P = 0.0012). In comparison to controls, the ratio of CD4(+)/CD8(+) lymphocytes was similar in both groups. The mean concentrations of sIL-2R in NPG (P = 0.011) and POAG (P = 0.0023) patients were higher than that found in control subjects although IL-2 concentrations were similar in these groups. In addition, the reactive ability of T lymphocytes to the non-specific reagent (PHA) was reduced significantly in NPG (P = 0.02) and POAG patients (P=0.04). CONCLUSION: The alterations of the cellular immune system in patients with glaucoma support our hypothesis that the immune system may play an important role in the initiation and/or sustainment of glaucomatous optic neuropathy in some patients.

Aged↗

PubMed2001

Automated detection of single nucleotide polymorphism in beta-2 adrenergic receptor gene using LCx(R).

Beta-2 adrenergic receptor (B2AR) agonists are the most widely prescribed rescue agents used in the treatment of asthma. Recent studies have indicated a relationship between a polymorphism at codon 16 of the B2AR gene, and the response to recurrent beta-agonist therapy. The B2AR polymorphism of interest involves a single nucleotide change from A to G, resulting in an amino acid change from Arginine (Arg) to Glycine (Gly). Clinical efforts to further investigate this relationship require an accurate, reliable and inexpensive method for detecting the polymorphism. In this study, we report an LCx(R) assay for the detection of a single nucleotide polymorphism at codon 16 of the beta-2 adrenergic receptor. This assay is capable of detecting patients harboring any of the three possible genotypes at this locus, namely, homozygous wild type, homozygous variant or heterozygous individuals with a single genomic DNA sample of 25-500 ng. It requires minimum hands-on time with automated detection. The assay would be suitable for use in research labs for screening of a large number of samples. We believe that this type of assay will facilitate research and clinical investigations in elucidating the association of SNPs with disease states, diagnosis, prognosis and treatment.

Adrenergic beta-Agonists↗

PubMed2001

Binding of an AMPA receptor potentiator ([3H]LY395153) to native and recombinant AMPA receptors.

LY395153 is a member of a newly described class of arylpropylsulfonamide AMPA receptor potentiators. Here, we characterize and compare [(3)H]LY395153 binding to native AMPA receptors from rat cerebral cortex and recombinant human GluR4(flip) receptors expressed in HEK293 cells. L-Glutamate and AMPA increased [(3)H]LY395153 binding to both native and recombinant AMPA receptors in a concentration dependent and stereoselective manner; this effect of AMPA receptor agonists reflects an apparent increase in ligand affinity. In the presence of L-glutamate (500 microM), [(3)H]LY395153 binding is saturable; the affinity of this radioligand is slightly, albeit statistically significantly higher at human GluR4(flip) (K(d)=55.6+/-5.3nM) than rat cortical receptors (K(d)=110+/-15.1nM). NBQX competitively inhibited L-glutamate-induced increases in [(3)H]LY395153 binding in both native and recombinant receptors, whilst LY303070 (the active isomer of GYKI53655) noncompetitively inhibited this effect in native, but not recombinant receptors. The prototypic AMPA receptor potentiator cyclothiazide competitively inhibited [(3)H]LY395153 binding with a potency (K(i) approximately 7 microM) comparable to EC(50) values reported in electrophysiological studies. In contrast, the structurally unrelated AMPA receptor potentiator CX 516 did not inhibit [(3)H]LY395153 binding at concentrations of up to 600 microM. Further, at concentrations reported to facilitate AMPA receptor desensitization, thiocyanate acts as a competitive inhibitor of [(3)H]LY395153 binding. [(3)H]LY395153 binding was unaffected by a variety of structurally (and mechanistically) diverse compounds tested at a concentration of 10 microM. These data indicate [(3)H]LY395153 is a useful probe for labeling a unique modulatory site on both native and recombinant AMPA receptors.

Allosteric Site↗

PubMed2001

Physiologic concentrations of magnesium and placental apoptosis: prevention by antioxidants.

OBJECTIVE: To identify the role of physiologic magnesium concentrations on the induction of placental apoptosis in vitro and test the anti-apoptotic action of antioxidants. METHODS: Placental tissue was obtained from normal pregnancies after cesarean delivery. Placental explants were incubated with increasing concentrations of extracellular magnesium (range 0-2.0 mM). Placental apoptosis was evaluated by tissue morphology, DNA fragmentation, cytokeratin-18 neoepitope formation, and cleavage of plasminogen activator inhibitor type 2. RESULTS: Physiologic concentrations of extracellular magnesium stimulated placental apoptosis. Magnesium stimulated apoptosis within the physiologic range (0.8-1.2 mM) (n = 6, P <.001) and was associated with cleavage of plasminogen activator inhibitor type 2 and cytokeratin-18 neoepitope formation. These data implicate caspase activation in the transduction of the magnesium-induced apoptotic signal. Therapeutic concentrations of vitamin C, vitamin E, and acetylcysteine (all at 25 microg/mL) inhibited DNA fragmentation and attenuated cleavage of plasminogen activator inhibitor type 2 and cytokeratin-18 neoepitope formation. CONCLUSION: Magnesium-induced placental apoptosis is a potent mechanism of placental degeneration in vitro and may represent an important regulator of placental tissue dynamics in vivo. The ability of antioxidants to prevent magnesium-induced placental apoptosis implicates oxidation-reduction-dependent signaling events in this process. Furthermore, these findings provide a basis for further studies of antioxidants in mitigating the adverse effects of preeclampsia.

Acetylcysteine↗

PubMed2001

Microbial ecotoxicity and mutagenicity of 1-hydroxypyrene and its photoproducts.

1-Hydroxypyrene (1-HP) is a carcinogenic and slightly water-soluble polycyclic aromatic hydrocarbon. Ecotoxicity and mutagenicity of 1-HP and its photoproducts, and the effect of Mn2+ and Cu2+ on their mutagenicity were measured with microbial assay in this study. The assay includes spread plate counting, direct counting, microbial mineralization of 14C-UL-D-glucose and Mutatox Test. At the concentration examined (0.8 microM), the photoproducts (after 1.5 h solar irradiation) of 1-HP inhibited microbial glucose mineralization activity (by 64%) after microbial assemblages of a local reservoir site were exposed for 1 day. However, heterotrophic bacteria were able to utilize 1-HP photoproducts as the growth substrates and increase viability counts by up to 4.75-folds. 1-HP exhibited positive response to Mutatox Test in both direct medium and S-9 medium, with the lowest observable effective concentration of 0.625 microM in the test with direct medium. After photolysis, 1-HP decreased its mutagenicity. Mn2+ (312.5 microM-5 mM) and Cu2+ (6.25-100 microM) themselves are not mutagenic. However, addition of the metal ions before or after photolysis modifies the light readings of 1-HP during the test. Therefore, presence of metal ions could affect the genotoxicity of 1-HP in aquatic environments, depending on timing of the addition.

Biological Assay↗

PubMed2001

Levels of insulin-like growth factor I (IGF-I) and IGF binding proteins 2 and 3 in serial postoperative serum samples and risk of prostate cancer recurrence.

OBJECTIVES: To determine changes of insulin-like growth factor I (IGF-I), IGF binding protein-2 (IGFBP-2), and IGFBP-3 levels in serial postoperative serum samples from prostate cancer patients with and without relapse and to evaluate the prognostic value of these molecules in the recurrence of prostate cancer. METHODS: From a group of patients with prostate cancer who had been followed for disease recurrence for almost 5 years after radical prostatectomy, we selected 38 patients (cases) who developed recurrent disease and 40 patients (controls) who were in remission. Of these patients, 70 had 4 and 8 had 3 serial postoperative serum samples collected. The median times for serum collection after surgery were 1.5 years for the first serial samples, 2.6 years for the second, 3.5 years for the third, and 4.5 years for the fourth. Serum levels of IGFBP-2, IGFBP-3, and IGF-I were measured, using commercial immunoassay kits. RESULTS: The study showed lower serum levels of IGFBP-2 and IGFBP-3 in the cases than in controls(P <0.05) but no difference in IGF-I levels between the two groups (P = 0.277). In the sequential samples, IGFBP-2 levels increased over time in the controls (P = 0.014) but did not change in the cases (P = 0.528). There were no increasing or decreasing trends for IGF-I and IGFBP-3 in either case or control group(P >0.05). CONCLUSIONS: The study suggests that IGFBP-2 may play a role in the progression of prostate cancer, but serum levels of IGFBP-2 as well as IGF-I and IGFBP-3 have no predictive values in the prognosis of prostate cancer.

Biomarkers, Tumor↗

PubMed2001

Fabrication of poly(phosphoester) nerve guides by immersion precipitation and the control of porosity.

Immersion precipitation was employed as a method for the fabrication of polymeric conduits from P(BHET-EOP/TC), a poly(phosphoester) with an ethylene terephthalate backbone, to be applied as guidance channels for nerve regeneration. Coatings of various porosities could be obtained by immersing mandrels coated with a solution of the polymer in chloroform into non-solvent immersion baths, followed by freeze or vacuum-drying. The porosity of the coatings decreased with an increase in polymer molecular weight, drying time before precipitation and concentration of polymer solution. The effects of these parameters can be rationalized by employing ternary phase diagrams, where porosity is directly related to the degree of phase separation available to the system before gelation occurs. To afford improved porosity control, a new system was developed which employed the contrasting phase-separation behavior of P(BHET-EOP/TC)/chloroform solution in methanol and water. As water is essentially a non-solvent for the polymer, the demixing boundary of the P(BHET-EOP/TC)-CHCl3-H2O system is located close to the polymer-solvent edge of the phase diagram, while that of the P(BHET-EOP/TC)-CHCl3-MeOH system is located further away. A mixture of methanol and water allows the demixing boundary to be shifted to intermediate coordinates. By immersing P(BHET-EOP/TC) coatings in immersion baths containing different ratios of water and methanol, then gradually titrating the bath with methanol to a concentration of 70% (v/v) methanol, surface porosities ranging from 2 to 58% could be achieved.

Biocompatible Materials↗

PubMed2001

A new nerve guide conduit material composed of a biodegradable poly(phosphoester).

There is a resurgence of interest in the development of degradable and biocompatible polymers for fabrication of nerve guide conduits (NGCs) in recent years. Poly(phosphoester) (PPE) polymers are among the attractive candidates in this context, in view of their high biocompatibility, adjustable biodegradability, flexibility in coupling fragile biomolecules under physiological conditions and a wide variety of physicochemical properties. The feasibility of using a biodegradable PPE, P(BHET-EOP/TC), as a novel NGC material was investigated. Two types of conduits were fabricated by using two batches of P(BHET-EOP/TC) with different weight-average molecular weights (Mw) and polydispersity indexes (PI). The polymers as well as conduits were non-toxic to all six types of cells tested, including primary neurones and neuronally differentiated PC12 cells. After in situ implantation in the sciatic nerve of the rat, two types of conduits triggered a similar tissue response, inducing the formation of a thin tissue capsule composed of approximately eight layers of fibroblasts surrounding the conduits at 3 months. Biological performances of the conduits were examined in the rat sciatic nerve model with a 10 mm gap. Although tube fragmentation, even tube breakage, was observed within less than 5 days post-implantation, successful regeneration through the gap occurred in both types of conduits, with four out of 10 in the Type I conduits (Mw 14,900 and PI 2.57) and 11 out of 12 in the Type II conduits (Mw 18,900 and PI 1.72). The degradation of conduits was further evidenced by increased roughness on the tube surface in vivo under scanning electron microscope and a mass decrease in a time-dependent manner in vitro. The Mw of the polymers dropped 33 and 24% in the Type I and II conduits, respectively, in vitro within 3 months. Among their advantages over other biodegradable NGCs, the PPE conduits showed negligible swelling and no crystallisation after implantation. Thus, these PPE conduits can be effective aids for nerve regeneration with potential to be further developed into more sophisticated NGCs that have better control of the conduit micro-environment for improved nerve regeneration.

Animals↗

PubMed2001

Differential regulation of neuropeptide Y receptors in the brains of NPY knock-out mice.

To study the effect of NPY deletion on the regulation of its receptors in the NPY knockout (NPY KO) mice, the expression and binding of NPY receptors were investigated by in situ hybridization and receptor autoradiography using (125)I-[Leu(31),Pro(34)]PYY and (125)I-PYY(3-36) as radioligands. A 6-fold increase in Y2 receptor mRNA was observed in the CA1 region of the hippocampus in NPY KO mice, but a significant change could not be detected for Y1, Y4, Y5 and y6 receptors. Receptor binding reveals a 60-400% increase of Y2 receptor binding in multiple brain areas. A similar increase in Y1 receptor binding was seen only in the hypothalamus. These results demonstrate the NPY receptor expression is altered in mice deficient for its natural ligand.

Animals↗

PubMed2001

Antibody-based sensors for heavy metal ions.

Competitive immunoassays for Cd(II), Co(II), Pb(II) and U(VI) were developed using identical reagents in two different assay formats, a competitive microwell format and an immunosensor format with the KinExA 3000. Four different monoclonal antibodies specific for complexes of EDTA-Cd(II), DTPA-Co(II), 2,9-dicarboxyl-1,10-phenanthroline-U(VI), or cyclohexyl-DTPA-Pb(II) were incubated with the appropriate soluble metal-chelate complex. In the microwell assay format, the immobilized version of the metal-chelate complex was present simultaneously in the assay mixture. In the KinExA format, the antibody was allowed to pre-equilibrate with the soluble metal-chelate complex, then the incubation mixture was rapidly passed through a microcolumn containing the immobilized metal-chelate complex. In all four assays, the KinExA format yielded an assay with 10-1000-fold greater sensitivity. The enhanced sensitivity of the KinExA format is most likely due to the differences in the affinity of the monoclonal antibodies for the soluble versus the immobilized metal-chelate complex. The KinExA 3000 instrument and the Cd(II)-specific antibody were used to construct a prototype assay that could correctly assess the concentration of cadmium spiked into a groundwater sample. Mean analytical recovery of added Cd(II) was 114.25+/-11.37%. The precision of the assay was satisfactory; coefficients of variation were 0.81-7.77% and 3.62-14.16% for within run and between run precision, respectively.

Antibodies, Monoclonal↗

PubMed2001

IGFBP-3 in epithelial ovarian carcinoma and its association with clinico-pathological features and patient survival.

Insulin-like growth factor binding protein-3 (IGFBP-3) regulates the mitogenic and anti-apoptotic actions of insulin-like growth factors (IGFs). To study the role of IGFBP-3 in ovarian cancer progression, we measured IGFBP-3 concentrations in tumour tissues from 147 patients with epithelial ovarian carcinoma and examined its associations with clinicopathological features of disease and patient survival. The average age of the patients was 54.6 years (range 25-88 years) and the median follow-up time was 37 months. IGFBP-3 levels were measured with a commercial immunoassay kit. Low IGFBP-3 levels were significantly associated with unfavourable prognostic features of the disease, including advanced stage (P=0.048), large size of residual tumour (P=0.007), and suboptimal debulking outcome (P=0.007). Low IGFBP-3 levels were also associated with a significantly increased risk for disease progression (RR=1.92; 95% confidence interval (CI) 1.05-3.45; P=0.034), but the association was not sustained when other clinical and pathological variables were adjusted for in the analysis. No significant associations were observed between the IGFBP-3 level and patients' overall survival and response to chemotherapy. Findings of the study indicate that IGFBP-3 may play a role in the progression of epithelial ovarian cancer, but that it has no independent value in predicting either disease prognosis or the response of patients to chemotherapy.

Adult↗

PubMed2001

GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells.

The p38 and JNK stress-activated MAPK signal transduction pathways are activated by T cell receptor (TCR) signaling and are required for IFN-gamma production by TH1 effector cells. Here, we show that the expression of GADD45gamma is induced during T cell activation and that the level of expression is higher in TH1 cells than in TH2 cells. TH1 cells from GADD45gamma(-/-) mice are severely compromised in their abilities to activate p38 and JNK in response to TCR signaling, produce much less IFN-gamma upon restimulation, and are deficient in activation-induced cell death (AICD). Additionally, GADD45gamma deficiencies caused reduced contact hypersensitivity in mice. Thus, GADD45gamma mediates activation of the p38 and JNK pathways and effector function of TH1 cells.

Animals↗

PubMed2001

Mad2-Independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1.

The mitotic checkpoint blocks the activation of the anaphase-promoting complex (APC) until all sister chromatids have achieved bipolar attachment to the spindle. A checkpoint complex containing BubR1 and Bub3 has been purified from mitotic human cells. Upon checkpoint activation, the BubR1-Bub3 complex interacts with Cdc20. In the absence of Mad2, BubR1 inhibits the activity of APC by blocking the binding of Cdc20 to APC. Surprisingly, the kinase activity of BubR1 is not required for the inhibition of APCCdc20. BubR1 also prevents the activation of APCCdc20 in Xenopus egg extracts, and restores the mitotic arrest in Cdc20-overexpressing cells treated with nocodazole. Because BubR1 also interacts with the mitotic motor CENP-E, the ability of BubR1 to inhibit APC may be regulated by kinetochore tension or occupancy.

Animals↗