Biomedical subjects

Lin Yang

Publications and source records attributed to Lin Yang.

At least 109 records · Page 6Linked to original sources

PubMed2004

Coordinated redistribution of leukocyte LFA-1 and endothelial cell ICAM-1 accompany neutrophil transmigration.

The leukocyte integrin lymphocyte function-associated antigen 1 (LFA-1) and its endothelial ligand intercellular adhesion molecule (ICAM)-1 play an important role in transmigration as demonstrated by in vivo and in vitro models of inflammation. Despite the prominent role, little is known concerning the distribution and dynamic behavior of these adhesion molecules during leukocyte transmigration. Therefore, we examined the spatial and temporal distribution of LFA-1 on neutrophils actively transmigrating tumor necrosis factor-alpha-activated human umbilical vein endothelial monolayers under shear flow. Upon neutrophil arrest, LFA-1 was evenly distributed. However, once neutrophils initiated transmigration, LFA-1 rapidly redistributed to form a ringlike cluster at the neutrophil-endothelial junctional interface through which transmigration occurred. As transmigration was completed, LFA-1 redistributed to the neutrophil uropod. Endothelial ICAM-1 and JAM-A both colocalized with the ringlike LFA-1 cluster. Further analysis of PMA-stimulated neutrophils, which increase mobility of LFA-1, showed a rapid redistribution of LFA-1 and ICAM-1, but not endothelial JAM-A. Thus, endothelial JAM-A does not appear to contribute to adhesion or transmigration in this system. This is the first demonstration that neutrophil LFA-1 rapidly redistributes to form a ringlike structure that coclusters with endothelial ICAM-1 as the neutrophil transmigrates.

Carcinogens↗

PubMed2004

Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms.

Voltage-dependent Ca(2+) channel (Ca(v)1.2, L-type Ca(2+) channel) function is highly regulated by hormones and neurotransmitters in large part through the activation of kinases and phosphatases. Regulation of Ca(v)1.2 by protein kinase C (PKC) is of significant physiologic importance, mediating, in part, the cardiac response to hormonal regulation. Although PKC has been reported to mediate activation and/or inhibition of Ca(v)1.2 function, the molecular mechanisms mediating the response have not been definitively elucidated. We show that PKC forms a macromolecular complex with the alpha(1c) subunit of Ca(v)1.2 through direct interaction with the C terminus. This interaction leads to phosphorylation of the channel in response to activators of PKC. We identify Ser(1928) as the residue that is phosphorylated by PKC in vitro and in vivo. Ser(1928) has been identified previously as the site mediating, in part, the protein kinase A up-regulation of channel activity. Thus, the protein kinase A and PKC signaling pathways converge on the Ca(v)1.2 complex at Ser(1928) to increase channel activity. Our results identify two mechanisms leading to regulation of Ca(v)1.2 activity by PKC: pre-association of the channel with PKC isoforms and phosphorylation of specific sites within the alpha(1c) subunit.

Animals↗

PubMed2004

Diffraction techniques for nonlamellar phases of phospholipids.

A neutron diffraction method applicable to nonlamellar phases of substrate-supported lipid membranes is described and validated. When prepared on a flat substrate, the resulting nonlamellar phases have layered symmetry which provides some advantages over powder diffraction for detailed structure determination. This approach recently led to the detection of a rhombohedral phase and a distorted hexagonal phase of lipids. Here the determination of intensity and phase information for such phases is demonstrated by application to the hexagonal phase of diphytanoyl phosphatidylcholine (DPhPC). The hexagonal symmetry is used to verify the data reduction procedure for the intensities of the diffraction peaks. Diffraction intensities measured while varying the D2O/H2O ratio in the relative humidity was used to solve the phase problem. The neutron scattering length density distribution of the hexagonal phase was constructed and analyzed to elucidate the packing of the lipid molecules. The structure of DPhPC in the hexagonal phase is of interest in connection with its stalk structure in the rhombohedral phase. We also found that the incorporation of tetradecane into the DPhPC hexagonal phase is limited, similar to the case for dioleoyl phosphatidylethanolamine.

Neutron Diffraction↗

PubMed2004

Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215.

The tumor suppressor p53 is important in the decision to either arrest cell cycle progression or induce apoptosis in response to a variety of stimuli. p53 posttranslational modifications and association with other proteins have been implicated in the regulation of its stability and transactivation activity. Here we show that p53 is phosphorylated by the mitotic kinase Aurora-A at serine 215. Unlike most identified phosphorylation sites of p53 that positively associate with p53 function (Brooks, C. L., and Gu, W. (2003) Curr. Opin. Cell Biol. 15, 164-171), the phosphorylation of p53 by Aurora-A at Ser-215 abrogates p53 DNA binding and transactivation activity. Downstream target genes of p53, such as p21Cip/WAF1 and PTEN, were inhibited by Aurora-A in a Ser-215 phosphorylation-dependent manner (i.e. phosphomimic p53-S215D lost and non-phosphorylatable p53-S215A retained normal p53 function). As a result, Aurora-A overrides the apoptosis and cell cycle arrest induced by cisplatin and gamma-irradiation, respectively. However, the effect of Aurora-A on p53 DNA binding and transactivation activity was not affected by phosphorylation of Ser-315, a recently identified Aurora-A phosphorylation site of p53 (Katayama, H., Sasai, K., Kawai, H., Yuan, Z. M., Bondaruk, J., Suzuki, F., Fujii, S., Arlinghaus, R. B., Czerniak, B. A., and Sen, S. (2004) Nat. Genet. 36, 55-62). Our data indicate that phosphorylation of p53 at Ser-215 by Aurora-A is a major mechanism to inactivate p53 and can provide a molecular insight for Aurora-A function.

Amino Acid Sequence↗

PubMed2004

Fatty acids increase presenilin-1 levels and [gamma]-secretase activity in PSwt-1 cells.

Presenilin-1 (PS1) is an important determinant of the gamma-secretase activity necessary for the generation of beta-amyloid (Abeta), likely the central pathogenic molecule in Alzheimer's disease. Most presenilin is rapidly degraded, and determinants of the level of the active cleaved form are unknown. We examined the influence of fatty acids on PS1 levels and gamma-secretase activity using stably transfected CHO cells that express human PS1 and the human amyloid precursor protein. Cells cultured with 0.4 mM oleic acid (OA), with 0.1 mM linoleic acid, or with a triglyceride emulsion expressed increased PS1 and Abeta. This effect was independent of any secondary increase in cellular cholesterol. Cells cultured in 0.4 mM OA also exhibited significantly increased gamma-secretase activity. PS1 mRNA levels were unchanged, and pulse-chase experiments indicated that OA slowed presenilin holoprotein degradation. Nontransfected human neuroblastoma cells also showed increased presenilin when cultured in 0.4 mM OA. Lipids may be important biological determinants of PS1 level and gamma-secretase activity.

Alzheimer Disease↗

PubMed2004

Role of CL-100, a dual specificity phosphatase, in thrombin-induced endothelial cell activation.

Using a cDNA microarray screening approach, we have identified seven novel thrombin-responsive genes in human umbilical vein endothelial cells that were verifiable by Northern blot analysis. Among them CL-100, a dual-specificity phosphatase also known as MAP kinase phosphatase-1 (MKP-1), showed greatest induction by thrombin. Steady-state levels of CL-100 mRNA induction by thrombin peaked at 1 h and declined rapidly (t1/2 approximately 45 min). Induction by thrombin was protease-activated receptor-1-mediated, protein synthesis-independent, and transcriptionally regulated. Metabolic labeling followed by immunoprecipitation verified that the thrombin-induced CL-100 mRNA was translated into protein. We found that both Src-kinase and p42/p44 ERK activity are critical for thrombin-induced CL-100 expression, whereas phosphatidylinositol 3-kinase and protein kinase C activity were not required. Antisense-mediated inhibition of CL-100 was shown to prolong thrombin-induced ERK activity in endothelial cells, concomitant with an inhibition in thrombin-induced PDGF-A (platelet-derived growth factor A) and PDGF-B gene expression and an up-regulation in thrombin-induced VCAM-1 and E-selectin gene expression. Inhibition of ERK activation by PD98059 in endothelial cells was shown to potentiate thrombin-induced expression of PDGF-B (approximately 3-fold) while inhibiting thrombin-induced VCAM-1 and E-selectin gene expression by 60 and 70%, respectively. These results suggested that induced expression of the CL-100 phosphatase and its subsequent regulation of ERK activity play a key regulatory role in the thrombin signaling pathway and in the transcriptional regulation of pathologically important "endothelial cell activation genes."

Blotting, Northern↗

PubMed2004

[Etiological dissection in common anti-islet autoantibody-negative patients with type 1 diabetes].

OBJECTIVE: To explore the immunological and genetic factors of common anti-islet autoantibody-negative patients with type 1 diabetes. METHODS: Specimens of peripheral blood were collected from 33 common autoantibody (GAD-Ab, IA2-Ab, IAA, TGA and TPO-Ab) negative diabetic patients with new-onset of unprovoked ketosis (or ketoacidosis), and genome DNA was extracted. The antibodies to carboxypeptide-H (CPH) and SOX13 (ICA12) were detected by radioligand assay. The gene mutations of MODY3 (HNF-1alpha) and MODY6 (NeuroD1/Beta2) were detected by PCR-SSCP sequencing. Mitochondrial gene mutations were analyzed with PCR-RFLP. RESULTS: Two (6%) of the patients were SOX13-Ab positive, while none of them was positive for CPH-Ab. Gene mutation detection found one case of a new mutation, R321H (CGC-->CAC) in the exon 5 of HNF-1alpha gene and one case with ND1 mt3316 G-->A mutation in mitochondrial DNA. In addition to the diabetes-associated mutations described above, seven polymorphisms of HNF-1alpha gene, including L17L, I27L, L459L, S487N, IVS5 + 9 C > G, IVS6-42 G > T, and IVS7 + 7 G > A, and one NeuroD1/Beta2 gene polymorphic variant Ala45Thr, were found. CONCLUSION: Autoimmunity and gene mutations (such as MODY3 and mitochondrial genes mutations) may be etiological in a few cases initially diagnosed as autoantibody-negative type 1 diabetes. Autoimmunity and MODY and mitochondrial diabetes should be excluded if idiopathic type 1 (type 1B) diabetes is diagnosed.

Adolescent↗

PubMed2004

Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt.

Accumulated studies have shown that activation of the Akt pathway plays a pivotal role in malignant transformation and chemoresistance by inducing cell survival, growth, migration, and angiogenesis. Therefore, Akt is believed to be a critical target for cancer intervention. Here, we report the discovery of a small molecule Akt pathway inhibitor, Akt/protein kinase B signaling inhibitor-2 (API-2), by screening the National Cancer Institute Diversity Set. API-2 suppressed the kinase activity and phosphorylation level of Akt. The inhibition of Akt kinase resulted in suppression of cell growth and induction of apoptosis in human cancer cells that harbor constitutively activated Akt due to overexpression of Akt or other genetic alterations such as PTEN mutation. API-2 is highly selective for Akt and does not inhibit the activation of phosphatidylinositol 3'-kinase, phosphoinositide-dependent kinase-1, protein kinase C, serum- and glucocorticoid-inducible kinase, protein kinase A, signal transducer and activators of transcription 3, extracellular signal-regulated kinase-1/2, or c-Jun NH(2)-terminal kinase. Furthermore, API-2 potently inhibited tumor growth in nude mice of human cancer cells in which Akt is aberrantly expressed/activated but not of those cancer cells in which it is not. These findings provide strong evidence for pharmacologically targeting Akt for anticancer drug discovery.

Animals↗

PubMed2004

Regulation of interleukin-6-mediated PI3K activation and neuroendocrine differentiation by androgen signaling in prostate cancer LNCaP cells.

BACKGROUND: Neuroendocrine (NE) differentiation in prostate cancer has been suggested to be one of the early events in the development of androgen independence. In the human prostate cancer LNCaP cell line, treatment with interleukin-6 (IL-6) induces NE-like differentiation, which is similar to the phenomena observed in advanced stages of prostate cancer progression. In this study, we investigate how androgen plays a role in IL-6-mediated NE differentiation in LNCaP cell line. METHODS: Western blot, co-immunoprecipitation (co-IP), and GST pull-down assays were performed to detect the protein expression and protein-protein interaction. PI3K kinase assay was used to measure PI3K activity. RESULTS: Addition of androgen blocks IL-6-mediated PI3K activation and NE differentiation in LNCaP cells. In vivo and in vitro protein interaction assays suggested that androgen receptor (AR) can directly interact with IL-6 transducer gp130. In addition, androgen treatment enhances the interaction between AR and gp130, interrupts the IL-6-induced gp130-mediated PI3K activation, which may lead to inhibition of IL-6-mediated NE differentiation in LNCaP cells. CONCLUSIONS: Our results suggest androgen and AR can regulate IL-6-mediated LNCaP cell NE differentiation via directly modulating the IL-6-PI3K pathway.

Blotting, Western↗

PubMed2004

Suppression of androgen receptor-mediated transactivation and cell growth by the glycogen synthase kinase 3 beta in prostate cells.

Androgens play important roles in the growth of normal prostate and prostate cancer via binding to the androgen receptor (AR). In addition to androgens, AR activity can also be modulated by selective growth factors and/or kinases. Here we report a new kinase signaling pathway by showing that AR transactivation was repressed by wild type glycogen synthase kinase 3beta (GSK3 beta) or constitutively active S9A-GSK3 beta in a dose-dependent manner. In contrast, the catalytically inactive kinase mutant GSK3 beta showed little effect on the AR transactivation. The suppression of AR transactivation by GSK3 beta was abolished by the GSK3 beta inhibitor lithium chloride. The in vitro kinase assay showed that GSK3 beta prefers to phosphorylate the amino terminus of AR that may lead to the suppression of activation function 1 activity located in the NH(2)-terminal region of AR. GSK3 beta interrupted the interaction between the NH(2) and COOH termini of AR, and overexpression of the constitutively active form of GSK3 beta, S9A-GSK3 beta, reduced the androgen-induced prostate cancer cell growth in stably transfected CWR22R cells. Together, our data demonstrated that GSK3 beta may function as a repressor to suppress AR-mediated transactivation and cell growth, which may provide a new strategy to modulate the AR-mediated prostate cancer growth.

Animals↗

PubMed2004

Assembly of a Ca2+-dependent BK channel signaling complex by binding to beta2 adrenergic receptor.

Large-conductance voltage and Ca2+-activated potassium channels (BKCa) play a critical role in modulating contractile tone of smooth muscle, and neuronal processes. In most mammalian tissues, activation of beta-adrenergic receptors and protein kinase A (PKAc) increases BKCa channel activity, contributing to sympathetic nervous system/hormonal regulation of membrane excitability. Here we report the requirement of an association of the beta2-adrenergic receptor (beta2AR) with the pore forming alpha subunit of BKCa and an A-kinase-anchoring protein (AKAP79/150) for beta2 agonist regulation. beta2AR can simultaneously interact with both BKCa and L-type Ca2+ channels (Cav1.2) in vivo, which enables the assembly of a unique, highly localized signal transduction complex to mediate Ca2+- and phosphorylation-dependent modulation of BKCa current. Our findings reveal a novel function for G protein-coupled receptors as a scaffold to couple two families of ion channels into a physical and functional signaling complex to modulate beta-adrenergic regulation of membrane excitability.

Animals↗

PubMed2004

The Kruppel-like KLF4 transcription factor, a novel regulator of urokinase receptor expression, drives synthesis of this binding site in colonic crypt luminal surface epithelial cells.

The urokinase-type plasminogen activator receptor (u-PAR) plays a central role in cell migration, growth, and invasion and is regulated, in part, transcriptionally. In mice, u-PAR expression is restricted to a few tissues, one of which is the colon. We therefore screened a colon expression library for regulators of u-PAR promoter activity and identified a zinc finger protein bearing consensus sequences to the Kruppel-like family of transcription factors and showing partial homology with one of the members, KLF4. Like u-PAR, KLF4 expression is predominant in the luminal surface epithelial cells of the colonic crypt, and we hypothesized that u-PAR synthesis in these cells is directed by this transcription factor. Colon cells from KLF4 null mice showed a dramatic reduction in u-PAR protein compared with wild-type mice. Conversely, KLF4 expression in HCT116 colon cancer cells increased the amount of u-PAR protein/mRNA. Transient transfection of KLF4 with a reporter driven by 5'-deleted u-PAR promoter fragments indicated the requirement of the proximal 200 base pairs for optimal expression. Mobility-shifting experiments demonstrated binding of KLF4 to multiple regions of the u-PAR promoter (-154/-128, -105/-71, and -51/-24), and chromatin immunoprecipitation assays confirmed the binding of KLF4 to the endogenous promoter. Deletion of the -144/-123 promoter region diminished but did not eliminate the ability of KLF4 to transactivate the u-PAR promoter, suggesting cooperativity of these binding sites with respect to activation of gene expression. In conclusion, we have identified KLF4 as a novel regulator of u-PAR expression that drives the synthesis of u-PAR in the luminal surface epithelial cells of the colon.

Alcian Blue↗

PubMed2004

Positive selection on multiple antique allelic lineages of transferrin in the polyploid Carassius auratus.

Transferrin polymorphism has been studied in the polyploid Carassius auratus by cloning and sequence analysis of cDNAs from its three subspecies C. auratus gibelio, C. auratus auratus, and C. auratus cuvieri. DNA polymorphism of extremely high extent was shown for the transferrin gene by the 248 segregation sites among coding region sequences of its alleles. The deduced amino acid sequences of the transferrin alleles showed variable theoretical physicochemical parameters, which might constitute molecular basis for their electrophoretic heterogeneity. Positive selection was inferred by the replacement/synonymous ratios larger than 1 in partial allelic lineages which was subsequently confirmed by likelihood simulation under neutral or selection models. Furthermore, the correspondent sites to these selected codons were collectively located at two planes in the crystallographic structure of rabbit transferrin, which suggested that the rapid evolution of C. auratus transferrin might correlate to its adaptation to variable environmental elements such as oxygen pressure. The minimal 26 recombination events were detected among coding sequences of C. auratus transferrin, with partial mosaic sequences and breakpoints identified by identity scanning and information site analyses. Phylogenetic analyses revealed multiple antique allelic lineages of transferrin, which was estimated to diverge fifteen to twenty MYA. All these features strongly suggested the role of balancing selection in long persistence of high transferrin polymorphism in C. auratus. Furthermore, owing to its particular evolutionary backgrounds, the silver crucian carp might possess a distinctive balancing selection mechanism.

Alleles↗

PubMed2004

Pathobiological behavior and molecular mechanism of signet ring cell carcinoma and mucinous adenocarcinoma of the stomach: a comparative study.

AIM: To elucidate the distinctive pathobiological behavior between signet ring cell carcinoma (SRC) and mucinous adenocarcinoma of the stomach. METHODS: Based on the histological growth patterns and cell-functional differentiation classifications of stomach carcinoma, we conducted a series of comparative studies. All paraffin-embedded and frozen blocks were collected from the files of Cancer Institute of China Medical University. On the basis of histopathological observation, we applied enzymatic and mucous histochemistry, immunohistochemistry, flow cytometry (FCM) and molecular biology to compare these two categories of gastric cancers in terms of the DNA ploidy, proliferative kinetics, the expression of gastric carcinoma associated gene product and instabilities of mitochondrial DNA (mtDNA). RESULTS: Gastric SRC was commonly seen in females below 45 years, mostly presenting diffuse growth and ovary or uterine cervix metastasis. The majority of SRC were absorptive and mucus-producing functional differentiation type (AMPFDT), which growth relied on estrogen. Meanwhile, stomach mucinous adenocarcinomas were mostly observed in males over 50 years, prone to massive growth or nest growth and extensive peritoneal infiltration, showing two categories of cell-functional differentiation types: AMPFDT and mucus-secreting functional differentiation type (MSFDT). Expressions of ER, enzyme c-PDE and 67kDaLN-R in SRC were evidently higher than that in mucinous adenocarcinoma, while expressions of LN, CN-IV, CD44v6, and PTEN protein were obviously lower in SRC than that in mucinous adenocarcinoma (P<0.05). There was no statistic significance in VEGF, ECD and instabilities of mtDNA (P>0.05) between the above two gastric carcinomas. CONCLUSION: Though SRC and mucinous adenocarcinoma were both characterized by abundant mucus-secretion, they were quite different in morphology, ultrastructure, cell-functional differentiation and protein expression, indicating different mechanisms of carcinogenesis. We concluded that combining histological growth patterns, cell-functional differentiation type with tumor related markers might be significant in early diagnosis and prognosis assessment for SRC and mucinous adenocarcinoma of the stomach.

Adenocarcinoma, Mucinous↗

PubMed2004

Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome.

Angiogenic factors are critical to the initiation of angiogenesis and maintenance of the vascular network. Here we use human genetics as an approach to identify an angiogenic factor, VG5Q, and further define two genetic defects of VG5Q in patients with the vascular disease Klippel-Trenaunay syndrome (KTS). One mutation is chromosomal translocation t(5;11), which increases VG5Q transcription. The second is mutation E133K identified in five KTS patients, but not in 200 matched controls. VG5Q protein acts as a potent angiogenic factor in promoting angiogenesis, and suppression of VG5Q expression inhibits vessel formation. E133K is a functional mutation that substantially enhances the angiogenic effect of VG5Q. VG5Q shows strong expression in blood vessels and is secreted as vessel formation is initiated. VG5Q can bind to endothelial cells and promote cell proliferation, suggesting that it may act in an autocrine fashion. We also demonstrate a direct interaction of VG5Q with another secreted angiogenic factor, TWEAK (also known as TNFSF12). These results define VG5Q as an angiogenic factor, establish VG5Q as a susceptibility gene for KTS, and show that increased angiogenesis is a molecular pathogenic mechanism of KTS.

Amino Acid Sequence↗

PubMed2004

Androgen suppresses PML protein expression in prostate cancer CWR22R cells.

The ability of PML to modulate key suppressive pathways in tumor cells suggests that PML may act as a tumor suppressor. The detailed mechanism of how PML functions in prostate cancer progression, however, remains unknown. Here we demonstrate that in the presence of androgen, PML protein expression can be suppressed in CWR22R prostate cancer cells. Further studies reveal that PML can selectively suppress AR transactivation and PML protein expression positively correlates with increased p21 protein level and enhances p53 transcription ability in CWR22R cells. We also found that PML strongly inhibits CWR22R cell colony formation, while PML siRNA enhances AR activity and CWR22R cell colony formation. Together our results suggest that PML may suppress prostate cancer cell growth by inhibiting AR transactivation and/or enhancing p53 activity.

Androgens↗

PubMed2004

Histogranin-like antinociceptive and anti-inflammatory derivatives of o-phenylenediamine and benzimidazole.

Histogranin (HN)-like nonpeptides were designed and synthesized using benzimidazole (compound 1) and o-phenylenediamine (compounds 2-7) as scaffolds for the attachment of phenolic hydroxyl and basic guanidino pharmacophoric elements present in HN. The benzimidazole derivative N-5-guanidinopentanamide-(2R)-yl-2-(p-hydroxybenzyl)-5-carboxybenzimidazole (1) and the o-phenylenediamine derivative N-5-guanidinopentanamide-(2S)-yl-2-N-(p-hydroxyphenylacetyl) phenylenediamine (2) were more potent analgesics than HN in both the mouse writhing (5.5 and 3.5 as potent as HN, respectively) and tail-flick (11.8 and 8.0 as potent as HN, respectively) pain assays. Improvements in the potencies and times of action of compound 2 in the mouse writhing test were obtained by attaching carboxyl (6)or p-Cl-benzoyl (7) groups at position 4 of the (2R) o-phenylenediamine derivative (5). In rats, compounds 2 (80 nmol i.t.), 6 (36 nmol i.t.), and 7 (18 nmol i.t.) were effective in blocking both persistent inflammatory pain in the formalin test and hyperalgesia in the complete Freund adjuvant assay. Compounds 2, 6, and 7, but not compound 1 at 10 nmol (i.c.v.) also mimicked the HN (60 nmol i.c.v.) blockade of N-methyl-D-aspartate (NMDA)-induced convulsions in mice. Finally, in primary cultures of rat alveolar macrophages, HN and compounds 1, 2, 6, and 7 (10(-8) M) significantly blocked lipopolysaccharide-induced cyclooxygenase-2 induction and prostaglandin E(2) secretion. These studies indicate that both derivatives of benzimidazole and o-phenylenediamine mimic the in vivo antinociceptive and in vitro anti-inflammatory effects of HN, but the HN protection of mice against NMDA-induced convulsions is mimicked only by the o-phenylenediamine derivatives.

Analgesics↗

PubMed2004

Alteration of the ATM gene occurs in gastric cancer cell lines and primary tumors associated with cellular response to DNA damage.

Ataxia telangiectasia mutated (ATM) is the gene mutated in the genetic disorder ataxia telangiectasia (AT), the symptoms of which include sensitivity to radiation and an increased risk of cancer. ATM is a kinase involved in activating the appropriate damage-response pathway, leading to either cell-cycle arrest or apoptosis, and is therefore a key checkpoint molecule in regulating cell-cycle response to DNA damage and responsible for maintenance of genome integrity. However, little is known about the association of ATM mutations with human gastric cancer (HGC). In order to determine the mutation and mRNA expression changes of the ATM gene in HGC, we performed analyses by denaturing high-performance liquid chromatography (DHPLC), DNA sequencing and RT-PCR technique on 13 human gastric tumor cell lines and 30 cases of fresh tumor specimens matched normal tissue. We compared the potential effect of the ATM gene mutation and cell behavior including cell-cycle arrest and induction of apoptosis in the tumor cell lines MGC803 and BGC823 with and without ionizing radiation (IR) exposure. Our data show that frequent variations were observed at 10 exons and 2 cDNA fragments which covered 8 other exons of the ATM gene as 5 out of 13 on the cell lines (38.5%) and 2 out of 30 cases in the tissue specimens (6.7%). All point mutations were confirmed as base substitutions (5982T-C; 6620A-G; 8684G-G/A; 9389C-G) and deletions (1079delC) by use of DNA sequencing. Among the mutations, one was reported previously in breast cancer, the other five have not yet been reported. The expression of ATM was significantly lower in five cell lines (MGC803; MKN45; SGC7901; GES and SUN-1) than in two others (BGC823 and RF48). G2/M cell-cycle arrest and apoptosis were observed in ATM-deficient MGC803 cells challenged with IR. A transient up-regulation of p53 occurred 1h post-IR in BGC823 cells but not in MGC803 cells. Our findings suggest that ATM mutations might be a pathogenic factor for an increased risk of gastric cancer, and the dysfunction of ATM may lead to a hypersensitivity to ionizing radiation in gastric cancer cells, possibly by a p53-dependent pathway.

Ataxia Telangiectasia Mutated Proteins↗