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)

ICAT inhibits the interaction between beta-catenin and TCF transcription factors. As ICAT might be a tumor suppressor gene with the potential to negatively regulate the WNT - beta-catenin - TCF signaling pathway, ICAT related gene in the human genome draft sequence was searched for. Here, the LZIC gene, a novel gene encoding a 190-amino-acid polypeptide with leucine zipper domain and ICAT homologous domain, was cloned and characterized. Amino-acid identity between LZIC and ICAT in the ICAT homologous domain was 38%. The LZIC gene, consisting of at least 8 exons, was located in the human chromosome 1p36.32-pter region. The major 5.2-kb LZIC mRNA and minor 2.1-, 1.6-, and 1.0-kb LZIC mRNAs were expressed almost ubiquitously in normal human tissues. LZIC was expressed in all cancer cell lines examined in this study, and was significantly up-regulated in a gastric cancer cell line MKN74 and 5 cases of primary gastric cancer. As LZIC contains ICAT homologous domain, LZIC might inhibit the interaction between beta-catenin and TCF transcription factors, just like ICAT, and, up-regulation of LZIC in gastric cancer might be due to a negative feed-back mechanism to inhibit the WNT - beta-catenin - TCF signaling pathway.
Int J Mol Med 2001 Dec
PMID:Molecular cloning and characterization of LZIC, a novel gene encoding ICAT homologous protein with leucine zipper domain. 1171 74

WNT2 is one of proto-oncogenes to activate the beta-catenin - TCF signaling pathway. WNT2B is a paralogue of WNT2, which encodes WNT2B1 and WNT2B2 isoforms due to alternative splicing using alternative promoter. Here, regulation of WNT2, WNT2B1, and WNT2B2 mRNAs in MCF-7 cells (breast cancer), NT2 cells (teratocarcinoma), and MKN45 cells (gastric cancer) were investigated. WNT2B2, but not WNT2 and WNT2B1, was expressed in MCF-7 cells. beta-estradiol (100 nM) induced a transient up-regulation of WNT2 in MCF-7 cells, and also induced down-regulation of WNT2B2. WNT2B2, but not WNT2B1, was expressed in NT2 cells, and WNT2 was slightly expressed in NT2 cells. Retinoic acid (10 microM) induced a transient up-regulation of WNT2 in NT2 cells. WNT2B2, but not WNT2 and WNT2B1, was slightly expressed MKN45 cells, and tumor necrosis factor alpha did not affect expression of WNT2, WNT2B1, and WNT2B2 mRNAs in MKN45 cells. This is the first report on differential regulation of WNT2, WNT2B1, and WNT2B2 mRNAs in human cancer cell lines. Up-regulation of WNT2 mRNA by estrogen might play a key role in some cases of human breast cancer through activation of the beta-catenin - TCF signaling pathway.
Int J Mol Med 2001 Dec
PMID:Differential regulation of WNT2 and WNT2B expression in human cancer. 1171 82

WNT signaling pathway is implicated in embryogenesis as well as in carcinogenesis. We have previously cloned and characterized Frizzled-1 (FZD1), FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, and FZD10, encoding seven-transmembrane-type WNT receptors. Here, expression of FZD10 mRNA in various types of human cancer and effects of FZD10 mRNA microinjection into Xenopus early embryos were investigated. Northern blot analyses revealed relatively high-level expression of 4.0-kb FZD10 mRNA in cervical cancer cell lines HeLa S3, SKG-I, SKG-IIIa, and in a glioblastoma cell line A-172. Matched tumor/normal expression array analysis revealed significant up-regulation of FZD10 mRNA in 2 cases of primary colon cancer. Function of FZD10 was next investigated by using Xenopus axis duplication assay, in which positive regulators of the WNT - beta-catenin - TCF signaling pathway induce axis duplication. Injection of wild-type FZD10 mRNA into the ventral marginal zone of 4-cell-stage Xenopus embryos induced partial axis duplication in 40% of embryos. Ventral injection of Thr579Ala FZD10 mRNA or Val581Leu FZD10 mRNA with mutations in the C-terminal Ser/Thr-X-Val motif also induced partial axis duplication in about 40% of embryos. Furthermore, ventral injection of FZD10 mRNA significantly augmented the potential of co-injected Xenopus wnt-8 (Xwnt-8) mRNA to induce complete axis duplication. These results suggest that up-regulation of FZD10 mRNA in several types of human cells might lead to carcinogenesis through activation of the beta-catenin - TCF signaling pathway synergistically with some class of WNTs.
Int J Mol Med 2002 Feb
PMID:Frizzled-10, up-regulated in primary colorectal cancer, is a positive regulator of the WNT - beta-catenin - TCF signaling pathway. 1178 18

SOX proteins are a family of transcription factors with high-mobility-group DNA-binding domain (HMG box) homologous to SRY, which are implicated in embryogenesis. Xenopus Sox17 alpha, Sox17 beta, and Sox3 are reported to negatively modulate the WNT - beta-catenin - TCF signaling pathway. Here, human SOX17 gene fragments were identified in human genome draft sequences by using bioinformatics, and SOX17 cDNAs were isolated by using cDNA-PCR. Human SOX17 was found to encode a 414-amino-acid protein with a HMG box, which was homologous to SOX18 and SOX7. SOX17 gene, consisting of 2 exons, was located in human chromosome 8q12-q13 region. SOX17 mRNAs of 2.5- and 2.2-kb in size were detected in adult heart, lung, spleen, testis, ovary, placenta, fetal lung, and kidney. In normal gastrointestinal tract, SOX17 mRNA was preferentially expressed in esophagus, stomach and small intestine than in colon and rectum. SOX17 mRNA was almost undetectable in human cancer cell lines HL-60, HeLa S3, K-562, MOLT-4, Raji, SW480, A549, G-361, and also in 66 cases of human primary tumors derived from various tissues, except one case of primary cervical cancer. This is the first report on molecular cloning and characterization of human SOX17.
Int J Mol Med 2002 Feb
PMID:Molecular cloning and characterization of human SOX17. 1178 26

Activation of Wnt signaling through beta-catenin/TCF complexes is a key event in the development of various tumors, in particular colorectal and liver tumors. Wnt signaling is controlled by the negative regulator conductin/axin2/axil, which induces degradation of beta-catenin by functional interaction with the tumor suppressor APC and the serine/threonine kinase GSK3beta. Here we show that conductin is upregulated in human tumors that are induced by beta-catenin/Wnt signaling, i.e., high levels of conductin protein and mRNA were found in colorectal and liver tumors but not in the corresponding normal tissues. In various other tumor types, conductin levels did not differ between tumor and normal tissue. Upregulation of conductin was also observed in the APC-deficient intestinal tumors of Min mice. Inhibition of Wnt signaling by a dominant-negative mutant of TCF downregulated conductin but not the related protein, axin, in DLD1 colorectal tumor cells. Conversely, activation of Wnt signaling by Wnt-1 or dishevelled increased conductin levels in MDA MB 231 and Neuro2A cells, respectively. In time course experiments, stabilization of beta-catenin preceded the upregulation of conductin by Wnt-1. These results demonstrate that conductin is a target of the Wnt signaling pathway. Upregulation of conductin may constitute a negative feedback loop that controls Wnt signaling activity.
Mol Cell Biol 2002 Feb
PMID:Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. 1180 9

For most ligand-dependent nuclear receptors, the status of endogenous ligand modulates the relative affinities for corepressor and coactivator complexes. It is less clear what parameters modulate the switch between corepressor and coactivator for the orphan receptors. Our previous work demonstrated that hepatocyte nuclear factor 4alpha1 (HNF4alpha1, NR2A1) interacts with the p160 coactivator GRIP1 and the cointegrators CBP and p300 in the absence of exogenously added ligand and that removal of the F domain enhances these interactions. Here, we utilized transient-transfection analysis to demonstrate repression of HNF4alpha1 activity by the corepressor silencing mediator of retinoid and thyroid receptors (SMRT) in several cell lines and on several HNF4alpha-responsive promoter elements. Glutathione S-transferase pulldown assays confirmed a direct interaction between HNF4alpha1 and receptor interaction domain 2 of SMRT. Loss of the F domain resulted in marked reduction of the ability of SMRT to interact with HNF4alpha1 in vitro and repress HNF4alpha1 activity in vivo, although the isolated F domain itself failed to interact with SMRT. Surprisingly, loss of both the A/B and F domains restored full repression by SMRT, suggesting involvement of both domains in the SMRT interaction. Finally, we show that when coexpressed along with HNF4alpha1 and GRIP1, CBP, or p300, SMRT can titer out HNF4alpha1-mediated transactivation in a dose-dependent manner and that this competition derives from mutually exclusive binding. Collectively, these results suggest that HNF4alpha can functionally interact with both a coactivator and a corepressor without altering the status of any putative ligand and that the presence of the F domain may play a role in discriminating between the different coregulators.
Mol Cell Biol 2002 Mar
PMID:Competitive cofactor recruitment by orphan receptor hepatocyte nuclear factor 4alpha1: modulation by the F domain. 1186 43

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

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

WNT signals are transduced to beta-catenin - TCF pathway, JNK pathway, or Ca2+-releasing pathway through WNT receptors. FRAT1, FRAT2, and PAR-1 are positive regulators of WNT - beta-catenin pathway. APC, AXIN, NKD1, NKD2, and Strabismus (STB1, STB2) are negative regulators of WNT - beta-catenin pathway. Here, biological significance of WNT3-WNT14B/WNT15 gene cluster (human chromosome 17q21) and WNT3A-WNT14 gene cluster (human chromosome 1q42) will be reviewed. Total-amino-acid identity between WNT3 and WNT3A is 84.2%, and that between WNT14 and WNT14B is 61.4%. WNT3A and WNT14B show reciprocal regulation by all-trans retinoic acid in NT2 cells and by beta-estradiol in MCF-7 cells. Exon-intron structures are well conserved between WNT3-WNT14B gene cluster and WNT3A-WNT14 gene cluster, except for the existence of an additional intron in 3'-UTR of WNT3. Capicua pseudogene and AK024248-related sequence are located within intergenic region of human WNT3A-WNT14 gene cluster, but not within intergenic regions of human WNT3-WNT14B gene cluster and mouse Wnt3a-Wnt14 gene cluster. Integration of mouse mammary tumor virus (MMTV) into mouse Wnt3-Wnt14b gene cluster leads to carcinogenesis. Because these WNT gene clusters might be fragile sites in the human genome, implication of WNT3 or WNT3A in cancer as well as implication of WNT14 or WNT14B in connective tissue disease and congenital joint malformation should be elucidated in the future. WNT3, WNT3A, WNT14, and WNT14B might be applicable to tissue engineering of neuron and joint in the field of regenerative medicine, and as an early diagnostic marker in the field of clinical oncology.
Int J Mol Med 2002 Jun
PMID:WNT3-WNT14B and WNT3A-WNT14 gene clusters (Review). 1201 73

The genetic causes of type 2 diabetes are not well understood. The disease has been linked to chromosome 20q12-q13.1 a region which harbors the transcription factor HNF4alpha. Mutations in the coding region of HNF4alpha cause maturity onset diabetes of the young, an autosomal dominant form of diabetes, but do not account for the linkage to this region. An enhancer element has recently been characterized 6 kb 5' of the HNF4alpha P1 promoter containing binding sites for the transcription factors HNF1, HNF4, HNF3, and C/EBP, which are overlapped by glucocorticoid consensus sites. We hypothesized that variation in the enhancer element disrupts HNF4alpha expression in the liver and increases susceptibility to type 2 diabetes. We screened for variants of the enhancer element in 39 white UK young onset diabetic subjects, giving >95% power to identify variants with minor allele frequencies of >5%. No variants of the enhancer element were found in this population. We conclude that variation in the HNF4alpha enhancer element is not a common cause of susceptibility to type 2 diabetes.
Mol Genet Metab 2002 Jun
PMID:The role of the HNF4alpha enhancer in type 2 diabetes. 1208 13


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