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Masaru Katoh

Publications and source records attributed to Masaru Katoh.

At least 73 records · Page 4Linked to original sources
PubMed2005

Comparative genomics on mammalian Fgf6-Fgf23 locus.

CCND2-C12orf5-FGF23-FGF6 locus at human chromosome 12p13.32 and CCND1-ORAOV1-FGF19-FGF4 locus at human chromosome 11q13.3 are paralogous regions (paralogons) within the human genome. FGF23 is the causative factor for tumor-induced osteomalacia (TIO), a paraneoplastic disorder characterized by hypophosphatemia and skeletal undermineralization, and also for autosomal dominant hypophosphatemic rickets (ADHR). Here, rat Fgf6 and Fgf23 complete coding sequences were determined by using bioinformatics. Rat Fgf6 and Fgf23 genes, consisting of three exons, were located within AC103292.6 rat genome sequence. Rat Fgf6 and Fgf23 genes were clustered in tail-to-head manner with an interval of about 52 kb. Human FGF6 and FGF23 genes were clustered in tail-to-head manner with an interval of about 54 kb. Intergenic conserved region (IGCR) within the FGF6-FGF23 gene cluster was identified based on the evolutionary conservation. Human FGF6-FGF23 IGCR (nucleotide position 111648-112242 of AC008012.8 genome sequence) and rat Fgf6-Fgf23 IGCR (nucleotide position 156318-156894 of AC103292.6 genome sequence) showed 77.6% total nucleotide identity. CP2, E47, CREB and PAX4 binding sites were conserved among human FGF6, rat Fgf6, and mouse Fgf6 promoters. GATA and E47 binding sites were conserved among human FGF23, rat Fgf23, and mouse Fgf23 promoters. Because mouse Fgf23 mRNA was expressed in dendritic cells and activated spleen, tumor infiltrating dendritic cells are candidate sources of FGF23 secretion in TIO patients. This is the first report on comparative genomics analyses on human FGF6-FGF23 gene cluster and rodents Fgf6-Fgf23 gene cluster.

Amino Acid Sequence↗
PubMed2005

Comparative genomics on SFRP1 orthologs.

SFRP1, SFRP2, SFRP3, SFRP4, SFRP5, WIF1, DKK1, DKK2, DKK3, DKK4 are secreted-type WNT signaling modulators. SFRP1 tumor suppressor gene at human chromosome 8p11.21 is inactivated in colorectal cancer and other tumors by deletion and by epigenetic CpG hypermethylation. Here, we identified and characterized the rat Sfrp1 gene by using bioinformatics. Rat Sfrp1 gene, consisting of three exons, was located within AC112899.4 genome sequence. Complete coding sequence of rat Sfrp1 was determined by assembling AC112899.4 genome sequence, CK838748 EST, and BF417482 EST. Rat Sfrp1 (314 aa) consisted of a signal peptide (codon 1-31), Frizzled domain with ten conserved Cys residues (codon 49-168), and Netrin (NTR) domain with six conserved Cys residues (codon 186-314). Rat Sfrp1 showed 98.7%, 95.2%, 94.3%, 82.5% and 58.3% total-amino-acid identity with mouse Sfrp1, human SFRP1, cow Sfrp1, chicken sfrp1 and zebrafish sfrp1, respectively. SFRP1 mRNA was expressed in embryonic stem (ES) cells, neuroblastoma, liver adeno-carcinoma, and skin squamous cell carcinoma. Match program revealed that AP1, COMP1, and double ETS1-binding sites were conserved between human SFRP1 and rat Sfrp1 promoters. This is the first report on comparative integromics analyses on Sfrp1 orthologs.

Amino Acid Sequence↗
PubMed2005

Comparative genomics on DKK2 and DKK4 orthologs.

WNT family proteins activate the beta-catenin - TCF pathway to induce carcinogenesis through cell fate determination, and also activate the planar cell polarity (PCP) pathway to induce cell motility and metastasis. DKK1, DKK2, DKK3 and DKK4 are secreted-type WNT signaling modulators belonging to the Dickkopf family. Here, we identified and characterized rat Dkk2 and Dkk4 genes by using bioinformatics. Rat Dkk2 and Dkk4 genes, consisting of four exons, were located within AC120263.4 and AC109661.6 genome sequences, respectively. Rat Dkk2 gene encoded a 259-aa protein, showing 95.8% total-amino-acid identity with human DKK2. Rat Dkk4 gene encoded a 221-aa protein, showing 75.4% total-amino-acid identity with human DKK4. Mammalian Dkk family members were secreted proteins with two Cys-rich regions, each containing ten conserved Cys residues. Asn-linked glycosylation site at codon 52 was conserved among mammalian Dkk2 orthologs; however, Asn-linked glycosylation site was not identified among mammalian Dkk4 orthologs. Dkk2 proteins were more conserved than Dkk4 proteins, while Dkk4 promoters were more conserved than Dkk2 promoters. TATA-box was identified within Dkk2 and Dkk4 promoters. MYOD and triple TCF/LEF binding sites were conserved between human DKK4 promoter and rodent Dkk4 promoter. DKK2 mRNA was expressed in Ewing's sarcoma, and fetal heart. DKK4 mRNA was expressed in human embryonic stem (ES) cells differentiated to an early endodermal cell type, breast cancer, and diffuse type gastric cancer. DKK4 orthologs are implicated in the negative feed back mechanism of the WNT/beta-catenin signaling pathway (the canonical WNT signaling pathway).

Amino Acid Sequence↗
PubMed2005

Comparative genomics on FGF8, FGF17, and FGF18 orthologs.

FGF and WNT signaling pathways network together during embryogenesis and carcinogenesis. Among 22 FGF family members within human and rodents genomes, FGF20 orthologs are evolutionarily conserved targets of the WNT/beta-catenin signaling pathway. FGF8, FGF17, and FGF18 constitute one of FGF subfamilies. Here, comparative proteomics and comparative genomics analyses on FGF8, FGF17, and FGF18 orthologs were performed. Rat Fgf8 and Fgf17 genes, consisting of five exons, were located within AC096326.7 and AC097410.12 genome sequences, respectively. FGF8, FGF17, and FGF18 orthologs were FGF family members with the N-terminal signal peptide. Human FGF8 isoform F showed 90.6% total-amino-acid identity with rat Fgf8 (268 aa). Human FGF17 showed 98.6% total-amino-acid identity with rat Fgf17 (216 aa). Human FGF18 also showed 98.6 total-amino-acid identity with rat Fgf18. FBXW1 (betaTRCP1 or BTRC1)-FGF8-NPM3 locus at human chromosome 10q24.32, FBXW11 (betaTRCP2 or BTRC2)-FGF18-NPM1 locus at human chromosome 5q35.1, and FGF17-NPM2 locus at human chromosome 8p21.3 were paralogous regions within the human genome. FGF8 mRNA was expressed in DMSO-treated embryonic stem (ES) cells. FGF17 mRNA was expressed in ES cells differentiated to an early endodermal phenotype. FGF18 mRNA was expressed in fetal lung, fetal heart, lung carcinoid, colorectal cancer, and ovarian cancer. FGF18 promoter with double TCF/LEF binding sites rather than FGF8 promoter and FGF17 promoter was more conserved between human and rodents. These facts indicate that FGF18 orthologs were evolutionarily conserved targets of the WNT/beta-catenin signaling pathway.

Amino Acid Sequence↗
PubMed2005

Comparative genomics on SFRP2 orthologs.

SFRP1, SFRP2, SFRP3, SFRP4, SFRP5, DKK1, DKK2, DKK3, DKK4, and WIF1 are soluble modulators of WNT signaling. SFRP2 gene at human chromosome 4q31.3 is claimed as a tumor suppressor gene inactivated by the epigenetic CpG hypermethylation in colorectal cancer. SFRP2 methylation is a sensitive single DNA-based marker for the fecal screening of colorectal cancer. On the other hand, SFRP2 is claimed to induce cellular resistance to apoptosis in mammary tumors. Here, we identified and characterized the rat Sfrp2 gene by using bioinformatics. Rat Sfrp2 gene, consisting of three exons, was located within AC129161.3 genome sequence. Rat Sfrp2 gene was found to encode a 295-aa Sfrp2 protein, consisting of signal peptide, Frizzled domain with ten conserved Cys residues, and Netrin (NTR) domain with six conserved Cys residues. Rat Sfrp2 showed 98.6% and 97.6% total-amino-acid identity with mouse Sfrp2 and human SFRP2, respectively. Phylogenetic analyses revealed that Sfrp2 orthologs were more related to Sfrp1 and Sfrp5 orthologs than to Sfrp3 and Sfrp4 orthologs. Human SFRP2 promoter (nucleotide position 71417-71152 of AC020703.7 genome sequence) and rat Sfrp2 promoter (nucleotide position 184090-184357 of AC129161.3 genome sequence) showed 88.7% total nucleotide identity. GC content of human SFRP2 promoter was 63.9%. Binding site for POU domain transcription factors (POU2F1, POU2F2, etc.) was conserved between human SFRP2 promoter and rat Sfrp2 promoter. SFRP2 mRNA was expressed in embryonic stem (ES) cells, diffuse type gastric cancer with signet ring cell features, pancreatic cancer, colorectal cancer, retinoblastoma, and insulinoma. This is the first report on comparative integromics analyses on SFRP2 orthologs.

Amino Acid Sequence↗
PubMed2005

Comparative genomics on SOX2 orthologs.

SOX2 and POU5F1 (OCT3 or OCT4) transcription factors are implicated in FGF4 expression in embryonic stem (ES) cells. SOX2, POU5F1, and FGF4 are key molecules for the integrome network in oncology and stem cell biology. SOX2 gene at human chromosome 3q26.33, SOX1 gene at 13q34, and SOX3 gene at Xq27.1 constitute a subfamily among the SOX gene family. Here, rat Sox2 and Xenopus sox2 genes were identified and characterized by using bioinformatics for comparative genomics and comparative proteomics analyses. Rat Sox2 gene, encoding a 319-aa protein, was located around the nucleotide position 73213-75621 of rat genome sequence AC123231.4. Xenopus tropicalis sox2 complete coding sequence, encoding a 311-aa protein, was derived from CR760314.1 cDNA. Rat Sox2 showed 98.4%, 97.8%, 92.2%, 88.1% and 86.8% total amino-acid identity with mouse Sox2, human SOX2, chicken sox2, Xenopus sox2 and zebrafish sox2, respectively. SOX123C domain was identified as the novel domain corresponding to the C-terminal region conserved among SOX1, SOX2 and SOX3 orthologs. Vertebrate SOX1, SOX2 and SOX3 orthologs were found consisting of HMG box and SOX123C domain. SOX9, TCF/LEF, POU2F1 and COMP1 binding sites were conserved among human SOX2 promoter, rat Sox2 promoter, and mouse Sox2 promoter. SOX2 mRNA was expressed in ES cells, fetal brain, anaplastic oligodendroglioma, rhabdomyosarcoma, and small cell lung carcinoma. Due to the pivotal role of SOX2 in the early embryogenesis, SOX2 promoter and SOX2 protein were well conserved during vertebrate evolution. This is the first report on comparative integromics analyses on the SOX2 orthologs.

Amino Acid Sequence↗
PubMed2005

Comparative genomics on SNAI1, SNAI2, and SNAI3 orthologs.

SNAI1, SNAI2, and SNAI3 genes, encoding transcriptional repressors implicated in epithelial mesenchymal transition (EMT), are human homologs of Drosophila snail (sna) and slug genes. SNAI1 represses transcription of CDH1 (E-cadherin) gene. SNAI2 induces the first phase of EMT, including desmosome dissociation, cell spreading, and initiation of cell separation. Because SNAI family proteins are implicated in EMT during embryogenesis and carcinogenesis, SNAI family genes are potent targets of pharmacogenomics. Here, comparative genomics analyses and comparative proteomics analyses on SNAI family orthologs were performed. Rat Snai3 gene, consisting of three exons, was identified within rat genome sequence AC111791.4. Zebrafish snai1a (NM_131066.1) was identified as SNAI1 ortholog. Chicken ChEST362l17 (CR407272.1), Xenopus slug (AF368041.1), and zebrafish zgc92564 (NM_001008581.1) were identified as SNAI2 orthologs. Chicken snail (NM_ 205142.1), Xenopus snail (BC056857.1), and zebrafish snai1b (NM_130989.1) were identified as SNAI3 orthologs. SNAI1 orthologs consisted of SNAG domain and four zinc finger (ZNF) domains, while SNAI2 and SNAI3 orthologs consisted of SNAG domain and five ZNF domains. Based on the integromics analyses, SNAI2 orthologs were found to be more conserved than SNAI1 and SNAI3 orthologs. SNAI1 mRNA was expressed in placenta, neuroblastoma, and diffuse type gastric cancer. SNAI2 mRNA was expressed in placenta, melanocyte, embryonic stem (ES) cells, leiomyosarcoma, neuroblastoma, and glioblastoma. SNAI3 mRNA was expressed in B cells. Expression of SNAI3 mRNA was repressed due to the existence of anti-sense single-exon transcript. SNAI1, functioning as E-cadherin repressor, is implicated in the malignant infiltrating phenotype of diffuse type gastric cancer through the induction of EMT or fibroblastoid transformation.

Amino Acid Sequence↗
PubMed2005

Comparative genomics on Sonic hedgehog orthologs.

Sonic hedgehog (SHH), Indian hedgehog (IHH), and Desert hedgehog (DHH) are key molecules for the integrome network in oncology and regenerative medicine. Soluble Hedgehog ligands bind to Patched receptor to activate Smoothened seven-transmembrane receptor with Frizzled domain. KIF27 and KIF7 are human homologs of Drosophila Costal-2 (Cos2), associating with Smoothened, GLI homolog, Fused, and microtubule. Smoothened activation leads to GLI1, GLI2, or GLI3-dependent transcription of Hedgehog target genes. Here, comparative proteomics analyses and comparative genomics analyses on SHH orthologs were performed by using bioinformatics. Human SHH representative transcript was assembled by using BX461534 EST, NM_000193.2 RefSeq, AA503654 EST, and AC078834.5 genome sequence. Human SHH mRNA was expressed in fetal brain, infant brain, and also in colorectal cancer. Chimpanzee SHH gene, consisting of three exons, was located within AC147335.2 genome sequence. Human SHH and chimpanzee SHH (462 aa) showed E284G and T416P amino-acid substitutions. Vertebrate SHH orthologs shared the common domain architecture, consisting of N-terminal signal peptide, Hedgehog signaling domain, Hint domain, and C-terminal HPLGMxxxxS motif. Evolutionarily conserved SHH promoter region (nucleotide position 104429-104083 of human genome sequence AC078834.5) was identified. Double bHLH binding sites, CCAAT box, and TATA box were conserved among human SHH promoter, chimpanzee SHH promoter, rat Shh promoter, and mouse Shh promoter.

Amino Acid Motifs↗
PubMed2005

Comparative genomics on FGF7, FGF10, FGF22 orthologs, and identification of fgf25.

FGF family members are key molecules for the integrome network in the fields of oncology and regenerative medicine. Based on the comparative genomics on the CCND1-ORAOV1-FGF19-FGF4 locus, we demonstrated that rodent Fgf15 is the ortholog of human FGF19 in 2003. FGF7 (KGF), FGF10, and FGF22 constitute a subfamily among FGF family members. Here, comparative genomics analyses and comparative proteomics analyses on FGF7, FGF10, and FGF22 orthologs were performed. Chicken fgf22, zebrafish fgf22 and fgf25 genes, consisting of three exons, were identified within AC150066.1, BX927243.9 and CR854981.2 genome sequences, respectively. Zebrafish fgf22 (207 aa) showed 46.9%, 48.6% and 53.5% total amino-acid identity with human FGF7, FGF10 and FGF22, respectively. Zebrafish fgf25 (186 aa) showed 39.2%, 52.9% and 45.9% total amino-acid identity with human FGF7, FGF10 and FGF22, respectively. Phylogenetic analyses revealed that zebrafish fgf25 belongs to the FGF10 ortholog group. Zebrafish fgf25 was a novel FGF family member generated by the duplication of fgf10. FGF10-MRPS30-HCN1 locus at human chromosome 5p12 and FGF22-POLRMT-HCN2 locus at 19p13.3 were paralogous regions within the human genome. FGF7 mRNA was expressed in fetal heart, placenta, lung, kidney, and blood vessels. FGF10 mRNA was expressed in fetal lung, placenta, and uterus. FGF22 mRNA was expressed in hippocampus and ovarian fibrotheoma. FGF7 promoter with bHLH biding site and CCAAT box and FGF10 promoter with double bHLH biding sites were conserved well, while FGF22 promoter was significantly divergent. This is the first report on fgf25 gene and also on the comparative integromics analyses of FGF7, FGF10 and FGF22 orthologs.

5' Flanking Region↗
PubMed2005

Comparative genomics on FGF16 orthologs.

We have previously reported comparative genomics analyses on FGF3, FGF4, FGF6, FGF7, FGF8, FGF10, FGF11, FGF17, FGF18, FGF19, FGF20, FGF22 and FGF23 genes. Here, we performed comparative genomics analyses on FGF1, FGF2, FGF5, FGF9, FGF12, FGF13, FGF14, FGF16 and FGF21 genes, and further characterized the FGF16 gene. Chimpanzee FGF16, chicken fgf16, and zebrafish fgf16 genes were identified within NW_121938.1, NW_060344.1, and CR855117.3 genome sequences, respectively. Chimpanzee FGF16 (207 aa), chicken fgf16 (207 aa), and zebrafish fgf16 (203 aa) showed 100%, 89.9%, and 79.2% total amino-acid identity with human FGF16. Because FGF16, FGF9, and FGF20 constitute FGF subfamily without N-terminal signal peptide, we next searched for uncharacterized FGF9 or FGF20 orthologs. Zebrafish fgf9 gene was identified within BX927112.11 genome sequence, and chicken fgf20 gene within NW_060349.1 genome sequence. Although N-terminal part was divergent, middle and C-terminal parts were well conserved among vertebrate FGF16, FGF9 and FGF20 orthologs. Phylogenetic analyses revealed that zebrafish fgf9 and fgf20 were more related to each other than to their chicken or mammalian orthologs. TCF/LEF binding site and TATA box were well conserved among the human FGF16, rat Fgf16, and mouse Fgf16 promoters. Because nuclear complex consisting of TCF/LEF (TCF1, TCF3, TCF4 or LEF1), beta-catenin, PYGO (PYGO1 or PYGO2) and Legless (BCL9 or BCL9L) binds to the TCF/LEF-binding site to up-regulate WNT/beta-catenin target genes, FGF16 gene was characterized as the evolutionarily conserved target of the WNT/beta-catenin signaling pathway, just like FGF18 and FGF20 genes. These facts indicate that FGF16, FGF18 and FGF20 are pharmacogenomics targets in the field of oncology and regenerative medicine.

Amino Acid Sequence↗
PubMed2005

Comparative genomics on SLIT1, SLIT2, and SLIT3 orthologs.

SLIT1 gene at human chromosome 10q24.1, SLIT2 gene at 4p15.31, and SLIT3 gene at 5q34-q35.1 encode large secreted proteins functioning as ligands for Roundabout (Robo) receptors. SLIT-ROBO signaling pathway is implicated in neurogenesis, angiogenesis, and immune response through the regulation of axonal guidance, endothelial cell migration, and denderitic cell migration, respectively. GREMLIN (CKTSF1B1 or GREM1) and DANTE (CKTSF1B3 or GREM3) are secreted antagonists for BMPs and SLITs. Here, comparative integromics analyses on SLIT1, SLIT2, and SLIT3 orthologs were performed by using bioinformatics. Rat Slit2 gene, consisting of 36 exons, was located within rat genome sequences AC098362.4 and AC111627.6. Mouse Slit3 complete coding sequence was determined by assembling BB634238 EST, AF144629 cDNA, and AK129223 cDNA. Leucine-rich repeats with nine conserved cysteine (LRRCC) domains and SLIT C-terminal cysteine-rich (SLITCCR) domain were identified in this study. CPxxCxCxxxxVxCxxxxLxxxPxxxPx(10~58) Nx(19,20)LxxNx(9)Fx(8)LxLxxNxxxCxxxxxFxxLxxx xxLxLxxNx(9)Fx(13)NxxxCxCxxxWLx(15)CxxPx(17)C was the consensus sequence of LRRCC domain. Mammalian SLIT1, SLIT2 and SLIT3 orthologs were large secreted proteins with four LRRCC domains, nine EGF domains, Laminin G (LamG) domain, and SLITCCR domain. SLIT1 mRNA was expressed in fetal brain, infant brain, anaplastic oligodendroglioma, and Jurkat T cells. SLIT2 and SLIT3 mRNAs were co-expressed in embryonic stem (ES) cells with embryoid body formation, and diffuse type gastric cancer with signet ring cell features. Double TCF/LEF and bHLH-binding sites were conserved among mammalian SLIT1 promoters. FOXJ2, E47, ETS1, and FOXA2-binding sites and CCAAT box were conserved among mammalian SLIT3 promoters. Mammalian SLIT1 orthologs were identified as evolutionarily conserved targets of the WNT/beta-catenin signaling pathway.

Amino Acid Sequence↗
PubMed2005

Epithelial-mesenchymal transition in gastric cancer (Review).

Endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), surgical gastrectomy, and chemotherapy are therapeutic options of gastric cancer; how-ever, prognosis of advanced gastric cancer patients is still poor. Gastric cancer cells with fibroblastoid morphological changes show increased motility and invasiveness due to decreased cell-cell adhesion, which are reminiscent of epithelial-mesenchymal transition (EMT) during embryonic development. Here, EMT signaling networks in gastric cancer were reviewed. E-cadherin at adherens junction is a key molecular target of EMT. CDH1 gene at human chromosome 16q22.1 encodes E-cadherin. Familial diffuse type gastric cancer occurs due to germ-line mutations of the CDH1 gene. Down-regulation of E-cadherin function due to mutation, deletion, CpG hyper-methylation, and SNAIL (SNAI1)- or SIP1-mediated transcriptional repression of the CDH1 gene leads to EMT in gastric cancer. Amplification of ERBB2, MET, FGFR2, PIK3CA, AKT1 genes, up-regulation of WNT2, WNT2B, WNT8B, and down-regulation of SFRP1 lead to EMT in gastric cancer through GSK3beta inhibition and following SNAIL-mediated CDH1 repression. Claudin (CLDN) and PAR3/PAR6/aPKC complex at tight junction are other key molecular targets of EMT. CLDN23 gene is down-regulated in intestinal type gastric cancer. Down-regulation of PAR3/PAR6/aPKC complex also leads to EMT. Single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) of genes encoding EMT signaling molecules will be identified as novel risk factors of gastric cancer. In addition, antibodies, RNAi compounds, and small molecular inhibitors for EMT signaling molecules will be developed as novel therapeutic agents for gastric cancer. Personalized medicine based on the combination of genetic screening and novel therapeutic agents could dramatically improve the prognosis of gastric cancer patients in the future.

Cadherins↗
PubMed2005

WNT/PCP signaling pathway and human cancer (review).

WNT/planar cell polarity (PCP) signaling pathway controls tissue polarity and cell movement through the activation of RHOA, c-Jun N-terminal kinase (JNK), and nemo-like kinase (NLK) signaling cascades. PCP is induced in Drosophila by the asymmetrical localization of Frizzled-Dishevelled-Diego-Starry night (Flamingo) complex and Van Gogh (Strabismus)-Prickle complex. Here, WNT/PCP signaling pathway implicated in human carcinogenesis is reviewed. Human WNT5A, WNT5B, and WNT11 are representative non-canonical WNTs transducing PCP signals through FZD3 or FZD6 receptors, and ROR1, ROR2 or PTK7 co-receptors. Human VANGL1, VANGL2 (Van Gogh homologs), CELSR1, CELSR2, CELSR3 (Starry night homologs), DVL1, DVL2, DVL3 (Dishevelled homologs), PRICKLE1, PRICKLE2 (Prickle homologs), and ANKRD6 (Diego homolog) are core PCP signaling molecules. MAGI3 assembles FZD, VANGL, PTEN, and adhesion molecules. Dishevelled-dependent WNT/PCP signals are transduced to the RHOA signaling cascade through Formin homology proteins DAAM1 and DAAM2, and to the JNK signaling cascade through MAPKKKs and MAPKK4/7. Dishevelled-independent WNT/ PCP signals are transduced to the NLK signaling cascade through MAP3K7 (TAK1). ANKRD6, NKD1 and NKD2 induce class switch from the WNT/GSK3beta signaling pathway to the WNT/PCP signaling pathway. WNT5A is up-regulated in various types of human cancer, such as gastric cancer, lung cancer, and melanoma. FZD3/FZD6 receptor and ROR2 co-receptor transduce WNT5A signal in gastric cancer. Aberrant activation of WNT/PCP signaling pathway in human cancer leads to more malignant phenotypes, such as abnormal tissue polarity, invasion, and metastasis. cDNA-PCR, microarray or ELISA reflecting aberrant activation of WNT/PCP signaling pathway could be developed as novel cancer prognostics. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of WNT/PCP signaling molecules mentioned above are suitable for use in screening of cancer predisposition, especially for gastric cancer. Antibody, RNAi, or small molecule compounds to regulate the function of WNT/PCP signaling molecules mentioned above are good candidates for development as novel cancer therapeutics.

Animals↗
PubMed2005

WNT2B: comparative integromics and clinical applications (Review).

We cloned and characterized human WNT2B (WNT13) in 1996. Following our discovery of human WNT2B, others and we characterized mouse, rat, chicken and zebrafish WNT2B orthologs. Here, comparative integromics analyses on WNT2B and its clinical applications are reviewed. WNT2B-ST7L-CAPZA1 locus at human chromosome 1p13.2 and WNT2-ST7-CAPZA2 locus at human chromosome 7q31.2 are paralogous regions within the human genome. Two splicing variants occur from human WNT2B gene due to alternative promoters. WNT2B splicing variant 1 encodes secreted-type glycoprotein with WNT domain (WNT2B isoform 1), while WNT2B splicing variant 2 encodes transmembrane-type glycoprotein with WNT domain (WNT2B isoform 2). WNT2B splicing variant 2 is the evolutionarily conserved major transcript of human WNT2B gene. Mammalian WNT2B orthologs acquired the transmembrane domain and integrin-targeting RGD motif during vertebrate evolution. Human WNT2B isoform 2 and other vertebrate WNT2B orthologs are canonical WNTs to determine cell fate through the activation of beta-catenin/TCF signaling pathway and SNAIL/EMT signaling pathway. E box and CCAAT box are conserved within mammalian WNT2B promoters. WNT2B functions as the stem cell factor for neural or retinal progenitor cells during embryogenesis, and also for gastric cancer, esophageal cancer and skin basal cell carcinoma during carcinogenesis. Anti-WNT2B monoclonal antibody could be applied as selection marker of stem cells in the field of stem cell biology. Soluble WNT2B protein or small molecule WNT2B mimic compounds could be developed for stem cell expansion in the fields of tissue engineering and regenerative medicine. Anti-WNT2B monoclonal antibodies, WNT2B RNAi compounds, or small molecule WNT2B inhibitors could be developed as novel therapeutic agents for gastric cancer and esophageal cancer in the field of clinical oncology.

Embryonic Development↗
PubMed2004

Coordination of chondrocyte differentiation and joint formation by alpha5beta1 integrin in the developing appendicular skeleton.

The control point by which chondrocytes take the decision between the cartilage differentiation program or the joint formation program is unknown. Here, we have investigated the effect of alpha5beta1 integrin inhibitors and bone morphogenetic protein (BMP) on joint formation. Blocking of alpha5beta1 integrin by specific antibodies or RGD peptide (arginine-glycine-aspartic acid) induced inhibition of pre-hypertrophic chondrocyte differentiation and ectopic joint formation between proliferating chondrocytes and hypertrophic chondrocytes. Ectopic joint expressed Wnt14, Gdf5, chordin, autotaxin, type I collagen and CD44, while expression of Indian hedgehog and type II collagen was downregulated in cartilage. Expression of these interzone markers confirmed that the new structure is a new joint being formed. In the presence of BMP7, inhibition of alpha5beta1 integrin function still induced the formation of the ectopic joint between proliferating chondrocytes and hypertrophic chondrocytes. By contrast, misexpression of alpha5beta1 integrin resulted in fusion of joints and formation of pre-hypertrophic chondrocytes. These facts indicate that the decision of which cell fate to make pre-joint or pre-hypertrophic is made on the basis of the presence or absence of alpha5beta1 integrin on chondrocytes.

Animals↗
PubMed2004

Pharmacogenomics on gastric cancer.

Gastric cancer is one of most common malignancies in the world. 5-fluoroyracil, CPT-11, TS-1, Paclitaxel and Docetaxel are used as chemotherapeutic agents for advanced gastric cancer, although endoscopic mucosal resection and surgical gastrectomy are potentially curative treatments. Most important problems associated chemotherapeutic agents are side effects and drug resistances. TSG101, implicated in membrane trafficking and transcriptional regulation, is upregulated in gastric cancer with multidrug resistant phenotype. Shen et al reported that transient transfection of TSG101 siRNA reduced the expression level of TSG101 protein as well as resistance to vincristine and adriamycin in gastric cancer cells. Bioinformatics, microarray analyses, SNP typing, and high-throughput functional analyses are applied for pharmacogenomics in the post-genome era. Therapeutics based on the genotyping of each patient is the future goal of personalized medicine (or tailor-made medicine) for gastric cancer.

Antineoplastic Agents↗
PubMed2004

Identification and characterization of human FNBP1L gene in silico.

FNBP1/FBP17/Rapostlin and TRIP10/CIP4 are structurally related microtubule-binding proteins involved in the regulation of cell shape, polarity, motility, and signal transduction. Here, we identified and characterized the FNBP1-like (FNBP1L) gene by using bioinformatics. Human FLJ20275 (NM_017737.1) and mouse 2610318I01Rik (NM_153118.1) were 5'-truncated partial cDNAs derived from human FNBP1L gene and mouse Fnbp1l gene, respectively. Exons 1-7 of FNBP1L gene were located within human genome sequence AL512651.13, and exons 7-15 within AL109613.11. Complete coding sequence of FNBP1L was determined in silico by assembling nucleotide sequences of FNBP1L exons. FNBP1L (547 aa) showed 59.4 and 55.4% total-amino-acid identity with FNBP1 and TRIP10, respectively. FNBP1L, FNBP1 and TRIP10 shared the common domain structure, consisting of FCH, FBH, HR1 and SH3 domains. FCH domain of FNBP1 family proteins is the microtubule-binding domain. HR1 (also known as antiparallel coiled-coil finger) is the binding domain for Rho family proteins, such as ARHN/RhoN and CDC42. SH3 domain of FNBP1 family proteins interacts with proline-rich region of Formin and WASP family proteins. FNBP1L gene was linked to SH2D3B/BCAR3 gene in tail-to-tail manner with an interval less than 8 kb within the human genome. FNBP1L-SH2D3B locus at human chromosome 1p22.1 was paralogous to GPR108-TRIP10-SH2D3A locus at 19p13.3 and GPR107-FNBP1-SH2D3C locus at 9q34.11-q34.13. This is the first report on comprehensive characterization of FNBP1L, which is predicted to function as a scaffold protein for microtubule, Rho family proteins, Formin-homology proteins and WAPS family proteins.

Amino Acid Sequence↗