Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The calcium-dependent homophilic cell adhesion molecule E-cadherin typically connects epithelial cells. The extracellular portion of the mature transmembrane protein consists of five homologous domains. The four sequences linking these domains contain the structural amino acid motif DXXD that is thought to be involved in direct calcium binding. In gastric cancer patients mutations affecting this motif between the second and third domain are frequently seen. In order to determine the functional significance of similar sequence alterations with regard to their location, we analyzed single amino acid substitutions changing the DXXD motif to DXXA in each linker region according to a mutation found in gastric cancer (D370A). The cDNA sequences coding for DQND, DVLD and DVND were changed (D257A, D479A, D590A, respectively) and stably expressed in E-cadherin negative MDA-MB-435S mammary carcinoma cells. We found that the D257A and D370A mutations result in abnormal protein localization, changes in the actin cytoskeleton, markedly reduced homophilic cell adhesion, and altered cell morphology. Unexpectedly, the tumor-associated D370A mutation but not the D257A mutation induced increased cell motility. The D479A mutation only had slight functional consequences whereas cells expressing the D590A mutant did not differ from cells expressing the wild-type molecule. Although the putative calcium binding motif DXXD is located at repetitive positions in the extracellular portion of E-cadherin, our results indicate that it has different functions depending on the location. Remarkably, tumor cells select for mutations in the most critical domains resulting both in loss of function (decreased cell adhesion) and in gain of function (increased cell motility). Since multiple DXXD motifs are typically seen in other cadherins, our structure-function study is relevant for this gene family in general.
J Mol Biol 2001 Nov 30
PMID:Single amino acid substitutions in conserved extracellular domains of E-cadherin differ in their functional consequences. 1184 58

SOX transcription factors with high-mobility-group DNA-binding domain (HMG box) play key roles in embryogenesis. Some members of the SOX family are negative regulators of the WNT-beta-catenin-TCF signaling pathway. We have previously cloned and characterized human SOX17, constituting a subfamily with SOX7 and SOX18. Another group mapped SOX7 gene to human chromosome 8p22, and reported almost ubiquitous expression of 5.0-kb SOX7 mRNA in human normal tissues. Here, expression of SOX7 mRNA was investigated by using SOX7 specific probe, which hybridized to 3.8-kb human SOX7 mRNA, but not to 5.0-kb mRNA. SOX7 mRNA was relatively highly expressed in adult lung, trachea, lymph node, placenta, fetal lung, and heart. In adult heart, SOX7 mRNA was more highly expressed in ventricules, inter-ventricular septum and apex than in atriums. SOX7 mRNA was significantly up-regulated in pancreatic cancer cell lines BxPC-3, PSN-1, Hs766T, and in 4 cases out of 8 cases of primary gastric cancer. SOX7 mRNA was relatively highly expressed in a gastric cancer cell line MKN45, esophageal cancer cell lines TE2, TE3, TE4, TE5, TE7, TE8, TE11, TE12, and TE13. On the other hand, SOX7 mRNA was significantly down-regulated in 7 out of 18 cases of primary colorectal tumors, in 4 out of 9 cases of primary breast cancer, in 4 out of 14 cases of primary kidney tumors, and also in some cases of primary lung and prostate cancer. SOX7 gene might be one of cancer-associated genes on human chromosome 8p22.
Int J Mol Med 2002 Apr
PMID:Expression of human SOX7 in normal tissues and tumors. 1189 28

This retrospective study was designed to assess the accuracy of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in diagnosing recurrence of gastric cancer. Thirty-three patients who had received surgical treatment for gastric cancer with curative intent and who had subsequently undergone FDG-PET for suspected recurrence were retrieved from the PET database. All patients were reviewed with full knowledge of prior conventional diagnostic work-up. Results were compared with a gold standard, consisting of histological confirmation or radiological and clinical follow-up. The gold standard established disease recurrence in 20/33 patients (prevalence 61%). Sensitivity and specificity of FDG-PET for the diagnosis of recurrence were 70% (14/20) and 69% (9/13), respectively. Positive and negative predictive values were 78% (14/18) and 60% (9/15), respectively. Of the six false-negative cases, all had intra-abdominal lesions (three had generalised abdominal metastases, one liver metastasis, one local recurrence and one ovarian metastasis). In the subgroup with previous signet cell differentiation of the primary tumour ( n=13, disease prevalence 62%), sensitivity was 62% (5/8) and specificity, 60% (3/5). Survival analysis for the entire patient group using Kaplan-Meier statistics yielded a longer survival in the PET-negative group (mean+/-SD, 21.9+/-19.0 months) than in the PET-positive group (mean+/-SD, 9.2+/-8.2 months) ( P=0.01). In the patient group with proven recurrence ( n=20), the mean survival for the PET-negative group was 18.5 (+/-12.5) months, as compared with 6.9 (+/-6.5) months for the PET-positive group ( P=0.05). Because of its poor sensitivity and low negative predictive value, FDG-PET is not suited for screening purposes in the follow-up of treated gastric cancer. However, FDG-PET appears to provide important additional information concerning the prognosis of recurrent gastric cancer.
Eur J Nucl Med Mol Imaging 2002 Apr
PMID:Whole-body PET with FDG for the diagnosis of recurrent gastric cancer. 1191 91

We have investigated the effects of ar-turmerone isolated from turmeric (Curcuma longa L) on DNA of human leukemia cell lines, Molt 4B, HL-60 and stomach cancer KATO III cells. It was found that selective induction of apoptosis by ar-turmerone was observed in human leukemia Molt 4B and HL-60 cells, but not in human stomach cancer KATO III cells. Morphological changes showing apoptotic bodies were observed in the human HL-60 and Molt 4B cells treated with ar-turmerone. The fragmentation of DNA by ar-turmerone to oligonucleosomal-sized fragments that is a characteristic of apoptosis was observed to be concentration- and time-dependent in Molt 4B and HL-60 cells, but not in KATO III cells. The data of the present study show that the suppression by ar-turmerone of growth of these leukemia cell lines results from the induction of apoptosis by this compound.
Int J Mol Med 2002 May
PMID:Selective induction of apoptosis by ar-turmerone isolated from turmeric (Curcuma longa L) in two human leukemia cell lines, but not in human stomach cancer cell line. 1195 52

GIPC1/RGS19IP1/GIPC, GIPC2, and GIPC3 are a family of central PDZ-domain proteins with GH1 and GH2 domains. GIPC1 interacts with GTPase-activating protein RGS19/RGS-GAIP, TGFbeta type III receptor, receptor tyrosine kinase TrkA, and integrin alpha6A subunit. Xenopus homologue of human GIPCs interacts with Frizzled-3 class of WNT receptor. We investigated expression of human GIPC1 mRNA in normal tissues, cancer cell lines, and primary tumors. GIP1A probe (nucleotide position 1075-1483 of GIPC1 cDNA) hybridized to GIPC1 mRNA of 1.8 kb in size. GIPC1 mRNA was almost ubiquitously expressed in various normal tissues. Expression level of GIPC1 mRNA was relatively lower in bone marrow and peripheral blood leukocytes. GIPC1 mRNA was relatively highly expressed in gastric cancer cell lines OKAJIMA, TMK1, MKN28, MKN45, MKN74, KATO-III, pancreatic cancer cell line AsPC-1, colorectal cancer cell line SW480, and lung cancer cell line A549. On the other hand, GIPC1 mRNA was almost undetectable in leukemia/lymphoma cell lines HL-60, Raji, and Daudi. Expression of GIPC1 mRNA was down-regulated in 12 out of 14 cases of primary kidney tumors, 10 out of 18 cases of primary colorectal tumors, 3 out of 8 cases of primary gastric cancer, 3 out of 3 cases of primary prostate cancer. Because GIPC1 induces increased expression of TGFbeta type III receptor at the cell surface and enhanced responsiveness to TGFbeta, down-regulation of GIPC1 mRNA in tumors might promote cellular proliferation through interference of TGFbeta signaling.
Int J Mol Med 2002 May
PMID:Expression of human GIPC1 in normal tissues, cancer cell lines, and primary tumors. 1195 58

WNT signal is transduced to the beta-catenin - TCF pathway, the JNK pathway, or the Ca2+-releasing pathway through seven-transmembrane-type WNT receptors encoded by Frizzled genes (FZD1-FZD10). We have previously cloned and characterized human WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT10A, WNT10B, WNT11, WNT14, and WNT14B/WNT15 by using bioinformatics, cDNA-library screening, and cDNA-PCR. Here, we investigated expression of human WNT5A mRNA in various normal tissues, 66 primary tumors derived from various tissues, and 15 human cancer cell lines. WNT5A mRNA was relatively highly expressed in salivary gland, bladder, uterus, placenta, and fetal kidney. Up-regulation of WNT5A mRNA was detected in 5 out of 8 cases of primary gastric cancer, 5 out of 18 cases of primary colorectal tumors, and in 2 out of 7 cases of primary uterus tumors by using matched tumor/normal expression array analysis. Up-regulation of WNT5A mRNA was also detected in 7 out of 10 other cases of primary gastric cancer by using cDNA-PCR. Although low-level expression of WNT5A mRNA was detected in gastric cancer cell line MKN45, WNT5A mRNA was almost undetectable in gastric cancer cell lines OKAJIMA, TMK1, MKN7, MKN28, MKN74, and KATO-III. Compared with frequent up-regulation of WNT5A mRNA in primary gastric cancer, expression levels of WNT5A mRNA in 7 gastric cancer cell lines were significantly lower than that in normal stomach. Frequent up-regulation of WNT5A mRNA in human primary gastric cancer might be due to cancer-stromal interaction.
Int J Mol Med 2002 May
PMID:Frequent up-regulation of WNT5A mRNA in primary gastric cancer. 1195 59

GIPC1/GIPC/RGS19IP1, GIPC2, and GIPC3 genes constitute the human GIPC gene family. GIPC1 and GIPC2 show 62.0% total-amino-acid identity. GIPC1 and GIPC3 show 59.9% total-amino-acid identity. GIPC2 and GIPC3 show 55.3% total-amino-acid identity. GIPCs are proteins with central PDZ domain and GIPC homology (GH1 and GH2) domains. PDZ, GH1, and GH2 domains are conserved among human GIPCs, Xenopus GIPC/Kermit, and Drosophila GIPC/ LP09416. Bioinformatics revealed that GIPC genes are linked to prostanoid receptor genes and DNAJB genes in the human genome as follows: GIPC1 gene is linked to prostaglandin E receptor 1 (PTGER1) gene and DNAJB1 gene in human chromosome 19p13.2-p13.1 region; GIPC2 gene to prostaglandin F receptor (PTGFR) gene and DNAJB4 gene in human chromosome 1p31.1-p22.3 region; GIPC3 gene to thromboxane A2 receptor (TBXA2R) gene in human chromosome 19p13.3 region. GIPC1 and GIPC2 mRNAs are expressed together in OKAJIMA, TMK1, MKN45 and KATO-III cells derived from diffuse-type of gastric cancer, and are up-regulated in several cases of primary gastric cancer. PDZ domain of GIPC family proteins interact with Frizzled-3 (FZD3) class of WNT receptor, insulin-like growth factor-I (IGF1) receptor, receptor tyrosine kinase TrkA, TGF-beta type III receptor (TGF-beta RIII), integrin alpha6A subunit, transmembrane glycoprotein 5T4, and RGS19/RGS-GAIP. Because RGS19 is a member of the RGS family that regulate heterotrimeric G-protein signaling, GIPCs might be scaffold proteins linking heterotrimeric G-proteins to seven-transmembrane-type WNT receptor or to receptor tyrosine kinases. Therefore, GIPC1, GIPC2 and GIPC3 might play key roles in carcinogenesis and embryogenesis through modulation of growth factor signaling and cell adhesion.
Int J Mol Med 2002 Jun
PMID:GIPC gene family (Review). 1201 74

Strabismus 1 (STB1/VANGL2) and Strabismus 2 (STB2/VANGL1), which have been cloned and characterized using bioinformatics and cDNA-PCR, are human homologues of Drosophila tissue polarity gene strabismus (stbm)/Van Gogh (Vang). STB1 and STB2 are tetra-membrane-spanning proteins with 73.1% total-amino-acid identity. Serine-rich domain and Strabismus-homology (STH1 and STH2) domains are conserved among human STB1, STB2, Xenopus Stbm, and Drosophila Stbm. STH2 domain with the C-terminal Ser/Thr-X-Val motif is implicated in binding with Dishevelled (DVL) proteins. STB1 gene is clustered with CASQ1 gene on human chromosome 1q21-q23, while STB2 gene is clustered with CASQ2 gene on human chromosome 1p13. STB1 and STB2 genes are located around cancer susceptibility loci or recombination hot spots in the human genome. STB1 is moderately expressed in K-562 (leukemia), G-361 (melanoma), and MKN7 (gastric cancer) cells. STB2 is highly expressed in MKN28, MKN74 (gastric cancer), BxPC-3, PSN-1, and Hs766T (pancreatic cancer) cells. On the other hand, STB1 and STB2 are significantly down-regulated in several cancer cell lines and primary tumors. Xenopus homologue of human STB1 and STB2 regulates negatively the WNT - beta-catenin signaling pathway. Loss-of-function mutations of genes encoding negative regulators of WNT - beta-catenin signaling pathway lead to carcinogenesis. Based on functional aspects and human chromosomal loci, STB1 gene and STB2 gene are predicted to be potent tumor suppressor gene candidates. STB1 and STB2 might be suitable targets for tissue engineering in the field of re-generative medicine and for chemoprevention and treatment in the field of clinical oncology.
Int J Mol Med 2002 Jul
PMID:Strabismus (STB)/Vang-like (VANGL) gene family (Review). 1206 Aug 45

During Drosophila hindgut development, bowl, caudal/CDX, brachyenteron/Brachyury/TBX, fork head/FOX, drumstick, lines, and wingless/WNT play important roles. Drosophila bowl gene is homologous to Drosophila odd-skipped (odd) gene and odd-skipped related gene (sob). Here, human OSR1, related to Drosophila odd, was isolated using bioinformatics and cDNA-PCR. OSR1 was found to encode 266 amino-acid protein with three C2H2-type zinc fingers, a tyrosine phosphorylation site (Tyr 203), and several putative PXXP SH3 binding motifs. Three zinc fingers and a tyrosine phosphorylation site were conserved among human OSR1, OSR2, Drosophila odd, sob, and bowl. OSR1 showed 63.6% total amino-acid identity with OSR2. OSR1 gene consisting of three exons was located on human chromosome 2p24. OSR1 mRNA of 2.3-kb in size was detected in adult colon, small intestine, prostate, testis, and fetal lung. OSR1 mRNA was significantly up-regulated in a pancreatic cancer cell line MIA PaCa-2, and was weakly expressed in gastric cancer cell lines OKAJIMA, MKN45, pancreatic cancer cell lines PANC-1, BxPC-3, AsPC-1, PSN-1, Hs766T, and esophageal cancer cell line TE10. Among 10 cases of primary gastric cancer, OSR1 mRNA was up-regulated in 5 cases, and was down-regulated in 2 cases. This is the first report on molecular cloning and characterization of human OSR1.
Int J Mol Med 2002 Aug
PMID:Molecular cloning and characterization of OSR1 on human chromosome 2p24. 1211 63

Among the many biological characteristics of cancer, matrix-metalloproteinases (MMPs) are essential for tumor invasion and metastasis. To test the possibility of ex vivo model as a therapeutic guideline for MMP inhibitor (MMPI) treatment, we evaluated IC50 of the gabexate mesylate against MMP-9. Thirty-four paired normal and gastric cancer tissues were tested to measure the IC50 of the gabexate mesylate. MMP-9 activity was measured by zymography. Both MMP-9 expression (p=0.04) and IC50 (p=0.02) were higher in cancer than normal tissues. IC50 of the cancer tissues was higher than paired normal tissues especially in cases with large tumor (> or =5 cm) (p=0.03), higher T-stage (p=0.04), lymph node metastasis (p=0.04) and advanced stage (p=0.04). In cancers extending beyond submucosa or in diffuse/mixed type, a tendency of higher IC50 was observed than tumors confined to submucosa or intestinal type cancer despite similar MMP-9 activity between the groups. Patients with high IC50 showed poorer prognosis than patients with low IC50 in curatively-resected group. In multivariate analysis, high IC50 was suggested as an independent prognostic factor. We were able to differentiate the high risk patients using IC50 of gabexate mesylate in ex vivo model. This model can be applied in detecting patients with poor prognosis and patients who may benefit from MMPI treatment.
Int J Mol Med 2002 Sep
PMID:Biological phenotype determination with ex vivo model in gastric cancer for matrix-metalloproteinase inhibitor treatment. 1216 96


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