Biomedical subjects

Yuriko Katoh

Publications and source records attributed to Yuriko Katoh.

At least 19 recordsLinked to original sources

PubMed2006

WNT antagonist, SFRP1, is Hedgehog signaling target.

Hedgehog and WNT signaling pathways network together during embryogenesis and carcinogenesis. Hedgehog signaling in intestinal epithelium represses canonical WNT signaling to restrict expression of WNT target genes to stem or progenitor cells; however, the mechanism remains unclear. The Hedgehog signal is transduced to GLI family transcription factors though Patched receptor, Smoothened signal transducer, and other signaling components, such as KIF27, KIF7, STK36, SUFU, and DZIP1. Here, we searched for the GLI-binding site within the promoter region of genes encoding secreted-type WNT signal inhibitors, including SFRP1, SFRP2, SFRP3, SFRP4, SFRP5, DKK1, DKK2, DKK3, DKK4, and WIF1. The GLI-binding site was identified within the human SFRP1 promoter based on bioinformatics and human intelligence. The chimpanzee SFRP1 gene was identified within the NW_110515.1 genome sequence. The GLI-binding site of the human SFRP1 promoter was conserved in chimpanzee SFRP1, mouse Sfrp1, and rat Sfrp1 promoters. SFRP1 is the evolutionarily conserved target of the Hedgehog-GLI signaling pathway. Expression domain analyses based on text mining revealed that Indian Hedgehog (IHH), SFRP1, and WNT6 are expressed in differentiated intestinal epithelial cells, mesenchymal cells, and stem/progenitor cells, respectively. Hedgehog is secreted from differentiated epithelial cells to induce SFRP1 expression in mesenchymal cells, which keeps differentiated epithelial cells away from the effects of canonical WNT signaling. These facts indicate that SFRP1 is the Hedgehog target to confine canonical WNT signaling within stem or progenitor cells. Therefore, epigenetic CpG hypermethylation of the SFRP1 promoter during chronic persistent inflammation and aging leads to the occurrence of gastrointestinal cancers, such as colorectal cancer and gastric cancer, through the breakdown of Hedgehog-dependent WNT signal inhibition.

Animals↗

PubMed2006

Comparative genomics on HHIP family orthologs.

Hedgehog, FGF, VEGF, and Notch signaling pathways network together for vascular remodeling during embryogenesis and carcinogenesis. HHIP1 (HHIP) is an endogenous antagonist for SHH, IHH, and DHH. Here, comparative integromics analyses on HHIP family members were performed by using bioinformatics and human intelligence. HHIP1, HHIP2 (HHIPL1 or KIAA1822) and HHIP3 (HHIPL2 or KIAA1822L) constitute human HHIP gene family. Rat Hhip1, Hhip2, and Hhip3 genes were identified within AC107504.4, AC094820.6, and AC134264.2 genome sequences, respectively. HHIP-homologous (HIPH) domain with conserved 18 Cys residues was identified as the novel domain conserved among mammalian HHIP1, HHIP2, and HHIP3 orthologs. HHIP1 mRNA was expressed in coronary artery endothelial cells, prostate, and rhabdomyosarcoma. HHIP2 mRNA was expressed in trabecular bone cells. HHIP3 mRNA was expressed in testis, thyroid gland, osteoarthritic cartilarge, pancreatic cancer, and lung cancer. Promoters of HHIP family genes were not well conserved between human and rodents. Although GLI-, CSL-, and HES/HEY-binding sites were not identified, eleven bHLH-binding sites were identified within human HHIP1 promoter. Expression of HES/HEY family members, including HES1, HES2, HES3, HES4, HES5, HES6, HES7, HEY1, HEY2 and HEYL, in coronary artery endothelial cells was not detected in silico. Up-regulation of HHIP1 due to down-regulation of Notch-CSL-HES/HEY signaling cascade repressing bHLH transcription factors results in down-regulation of the Hedgehog-VEGF-Notch signaling cascade. On the other hand, down-regulation of HHIP1 due to up-regulation of Notch signaling in vascular endothelial cells during angiogenesis results in up-regulation of the Hedgehog-VEGF-Notch signaling cascade. Because HHIP1 is the key molecule for vascular remodeling, HHIP1 is the pharmacogenomics target in the fields of oncology and vascular medicine.

Amino Acid Sequence↗

PubMed2006

FGF signaling inhibitor, SPRY4, is evolutionarily conserved target of WNT signaling pathway in progenitor cells.

WNT, FGF and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. FGF16, FGF18, and FGF20 genes are targets of WNT-mediated TCF/LEF-beta-catenin-BCL9/BCL9L-PYGO transcriptional complex. SPROUTY (SPRY) and SPRED family genes encode inhibitors for receptor tyrosine kinase signaling cascades, such as those of FGF receptor family members and EGF receptor family members. Here, transcriptional regulation of SPRY1, SPRY2, SPRY3, SPRY4, SPRED1, SPRED2, and SPRED3 genes by WNT/beta-catenin signaling cascade was investigated by using bioinformatics and human intelligence (humint). Because double TCF/LEF-binding sites were identified within the 5'-promoter region of human SPRY4 gene, comparative genomics analyses on SPRY4 orthologs were further performed. SPRY4-FGF1 locus at human chromosome 5q31.3 and FGF2-NUDT6-SPATA5-SPRY1 locus at human chromosome 4q27-q28.1 were paralogous regions within the human genome. Chimpanzee SPRY4 gene was identified within NW_107083.1 genome sequence. Human, chimpanzee, rat and mouse SPRY4 orthologs, consisting of three exons, were well conserved. SPRY4 gene was identified as the evolutionarily conserved target of WNT/beta-catenin signaling pathway based on the conservation of double TCF/LEF-binding sites within 5'-promoter region of mammalian SPRY4 orthologs. Human SPRY4 mRNA was expressed in embryonic stem (ES) cells, brain, pancreatic islet, colon cancer, head and neck tumor, melanoma, and pancreatic cancer. WNT signaling activation in progenitor cells leads to the growth regulation of progenitor cells themselves through SPRY4 induction, and also to the growth stimulation of proliferating cells through FGF secretion. Epigenetic silencing and loss-of-function mutations of SPRY4 gene in progenitor cells could lead to carcinogenesis. SPRY4 is the pharmacogenomics target in the fields of oncology and regenerative medicine.

Amino Acid Sequence↗

PubMed2006

Comparative integromics on Ephrin family.

EFNA1, EFNA2, EFNA3, EFNA4, EFNA5, EFNB1, EFNB2 and EFNB3 are EFN family ligands for EPH family receptors. EFN/EPH signaling pathway networks with the WNT signaling pathway during embryogenesis, tissue regeneration, and carcinogenesis. Comparative genomics analyses on EFNB1, EFNB2 and EFNB3 were performed by using bioinformatics and human intelligence (humint). EFNB1 mRNA was expressed in human embryonic stem (ES) cells, neural tissues, diffuse type gastric cancer, pancreatic cancer, colon cancer, brain tumors and esophageal cancer, EFNB2 mRNA in human ES cells, neural tissues and colon cancer, EFNB3 mRNA in human ES cells, neural tissues, brain tumors, pancreatic cancer and colon cancer. Because triple TCF/LEF-binding sites were identified within the 5'-promoter region of human EFNB3 gene, comparative genomics analyses on EFNB3 orthologs were further performed. Chimpanzee EFNB3 gene, consisting of five exons, was identified within AC164921.3 genome sequence. AY421228.1 was not a correct coding sequence for chimpanzee EFNB3. Chimpanzee EFNB3 gene was found to encode a 340-amino-acid protein showing 99.4% and 96.6% total-amino-acid identity with human EFNB3 and mouse Efnb3, respectively. Three TCF/LEF-binding sites within human EFNB3 promoter were conserved in chimpanzee EFNB3 promoter, and the second TCF/LEF-binding site in rodent Efnb3 promoters. CpG hypermethylation of EFNB3 promoter with 63.2% GC content as well as deletion of EFNB3 gene closely linked to TP53 tumor suppressor gene at human chromosome 17p13.1 should be investigated to elucidate the mechanism of infrequent EFNB3 upregulation in human colorectal cancer. EFNB3, identified as potential transcriptional target of WNT/beta-catenin signaling pathway, is a pharmacogenomics target in the fields of regenerative medicine and oncology.

Amino Acid Sequence↗

PubMed2006

Comparative integromics on BMP/GDF family.

WNT, Notch, FGF, Hedgehog and BMP signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP15, AMH, GDF1, GDF2, GDF3, GDF5, GDF6, GDF7, GDF8, GDF9, GDF10, GDF11, and GDF15 are BMP/GDF family genes within the human genome; however, transcriptional regulation of BMP/GDF family members by the canonical WNT signaling pathway remains unclear. We searched for the TCF/LEF-binding site within the promoter region of BMP/GDF family genes by using bioinformatics and human intelligence. Because four TCF/LEF-binding sites were identified within human GDF10 promoter, comparative genomics analyses on GDF10 orthologs were further performed. Chimpanzee GDF10 gene, encoding a 477-amino-acid protein, was identified within NW_112875.1 genome sequence. AY412135.1 was not the correct coding sequence for chimpanzee GDF10. Chimpanzee GDF10 showed 99.2%, 83.2% and 47.4% total amino-acid identity with human GDF10, mouse Gdf10 and human BMP3, respectively. RASGEF1A-GDF10-PRKG1 locus at human chromosome 10q11 and BMP3-PRKG2-RASGEF1B locus at human chromosome 4q21 were paralogous regions with insertions/deletions and recombination. Human GDF10 mRNA was expressed in fetal cochlea, fetal lung, testis, retina, pineal gland, other neural tissues, head and neck tumors, while mouse Gdf10 mRNA was expressed in fetal liver, inner ear, cerebellum, other neural tissues, prostate and blood vessels. Four TCF/LEF-binding sites in human GDF10 promoter were conserved in chimpanzee GDF10 promoter, but not in the mouse Gdf10 promoter; however, another TCF/LEF-binding site occurred in mouse Gdf10 promoter. Four bHLH-binding sites in human GDF10 promoter were conserved in chimpanzee GDF10 promoter, but only one in mouse Gdf10 promoter. Primate GDF10 promoters were divergent from mouse Gdf10 promoter. Because GDF10 was characterized as a potential target of canonical WNT signaling pathway in neural tissues, GDF10 is one of the targets of systems medicine, especially in the field of regenerative medicine.

Amino Acid Sequence↗

PubMed2006

Comparative integromics on Angiopoietin family members.

Angiopoietin-1 (ANGPT1), Angiopoietin-4 (ANGPT4), VEGF, FGF2, FGF4, HGF, Ephrin, IL8 and CXCL12 (SFD1) are pro-angiogenic factors (angiogenic activators), while Angiopoietin-2 (ANGPT2), Angiostatin, Endostatin, Tumstatin, Canstatin, THBS1, THBS2, TNFSF15 (VEGI) and Vasohibin (VASH1) are anti-angiogenic factors (angiogenic inhibitors). ANGPT1 and ANGPT2 are ligands for TIE family receptor tyrosine kinases, TIE1 and TIE2 (TEK). Angiopoietin family consists of ANGPT1, ANGPT2, ANGPT4, ANGPTL1 (ANGPT3), ANGPTL2, ANGPTL3 (ANGPT5), ANGPTL4, ANGPTL5, ANGPTL6 and ANGPTL7. TCF/LEF binding sites within the promoter region of human Angiopoietin family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the human ANGPTL7 promoter, comparative genomics analyses on ANGPTL7 orthologs were further performed. ANGPTL7 gene at human chromosome 1p36.22 was located within intron 28 of FRAP1 gene encoding mTOR protein. Chimpanzee ANGPTL7 gene, consisting of five exons, was located within NW_101546.1 genome sequence. Chimpanzee ANGPTL7 showed 99.4% and 86.1% total-amino-acid identity with human ANGPTL7 and mouse Angptl7, respectively. Human ANGPTL7 mRNA was expressed in neural tissues, keratoconus cornea, trabecular meshwork, melanotic melanoma and uterus endometrial cancer, while mouse Angptl7 mRNA was expressed in four-cell embryo, synovial fibroblasts, thymus, uterus and testis. Four TCF/LEF-binding sites within human ANGPTL7 promoter were conserved in chimpanzee ANGPTL7 promoter; however, only an unrelated TCF/LEF-binding site occurred in mouse and rat Angptl7 promoters. Human ANGPTL7, characterized as potent target gene of WNT/ beta-catenin signaling pathway, is a pharmacogenomics target in the fields of oncology and regenerative medicine.

Angiopoietins↗

PubMed2006

Canonical WNT signaling pathway and human AREG.

AREG (Amphiregulin), BTC (beta-cellulin), EGF, EPGN (Epigen), EREG (Epiregulin), HBEGF, NRG1, NRG2, NRG3, NRG4 and TGFA (TGFalpha) constitute EGF family ligands for ERBB family receptors. Cetuximab (Erbitux), Pertuzumab (Omnitarg) and Trastuzumab (Herceptin) are anti-cancer drugs targeted to EGF family ligands, while Gefitinib (Iressa), Erlotinib (Tarceva) and Lapatinib (GW572016) are anti-cancer drugs targeted to ERBB family receptors. AREG and TGFA are biomarkers for Gefitinib non-responders. The TCF/LEF binding sites within the promoter region of human EGF family members were searched for by using bioinformatics and human intelligence (Humint). Because three TCF/LEF-binding sites were identified within the 5'-promoter region of human AREG gene, comparative genomics analyses on AREG orthologs were further performed. The EPGN-EREG-AREG-BTC cluster at human chromosome 4q13.3 was linked to the PPBP-CXCL segmental duplicons. AREG was the paralog of HBEGF at human chromosome 5q31.2. Chimpanzee AREG gene, consisting of six exons, was located within NW_105918.1 genome sequence. Chimpanzee AREG was a type I transmembrane protein showing 98.0% and 71.4% total amino-acid identity with human AREG and mouse Areg, respectively. Three TCF/LEF-binding sites within human AREG promoter were conserved in chimpanzee AREG promoter, but not in rodent Areg promoters. Primate AREG promoters were significantly divergent from rodent Areg promoters. AREG mRNA was expressed in a variety of human tumors, such as colorectal cancer, liver cancer, gastric cancer, breast cancer, prostate cancer, esophageal cancer and myeloma. Because human AREG was characterized as potent target gene of WNT/beta-catenin signaling pathway, WNT signaling activation could lead to Gefitinib resistance through AREG upregulation. AREG is a target of systems medicine in the field of oncology.

Amino Acid Sequence↗

PubMed2006

Comparative integromics on VEGF family members.

VEGF, Hedgehog, FGF, Notch, and WNT signaling pathways network together for vascular remodeling during embryogenesis, tissue regeneration, and carcinogenesis. VEGFA (VEGF), VEGFB, VEGFC, VEGFD (FIGF) and PGF (PlGF) are VEGF family ligands for receptor tyrosine kinases, including VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4). Bevacizumab (Avastin), Sunitinib (Sutent) and Sorafenib (Nexavar) are anti-cancer drugs targeted to VEGF signaling pathway. TCF/LEF binding sites within the promoter region of human VEGF family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the 5'-promoter region of human VEGFD gene within AC095351.5 genome sequence, comparative genomics analyses on VEGFD orthologs were further performed. ASB9-ASB11-VEGFD locus at human chromosome Xp22.2 and ASB5-VEGFC locus at human chromosome 4q34 were paralogous regions within the human genome. Human VEGFD mRNA was expressed in lung, small intestine, uterus, breast, neural tissues, and neuroblastoma. Mouse Vegfd mRNA was expressed in kidney, pregnant oviduct, and neural tissues. Chimpanzee VEGFD promoter, cow Vegfd promoter, mouse Vegfd promoter and rat Vegfd promoter were identified within NW_121675.1, AC161065.2, AL732475.6 and AC130036.3 genome sequences, respectively. Three out of four TCF/LEF-binding sites within human VEGFD promoter were conserved in chimpanzee VEGFD promoter, and one in cow Vegfd promoter. TCF/LEF-binding site, not conserved in human VEGFD promoter, occurred in cow, mouse and rat Vegfd promoters. At least five out of six bHLH-binding sites within human VEGFD proximal promoter region were conserved in chimpanzee VEGFD proximal promoter region, while only one in cow Vegfd proximal promoter region. Together these facts indicate that relatively significant promoter evolution occurred among mammalian VEGFD orthologs. Human VEGFD was characterized as a potent target gene of WNT/beta-catenin signaling pathway. VEGFD, implicated in angiogenesis and lymphatic metastasis, is a pharmacogenomics target in the field of oncology.

Base Sequence↗

PubMed2006

Comparative integromics on FAT1, FAT2, FAT3 and FAT4.

WNT5A, WNT5B, WNT11, FZD3, FZD6, VANGL1, VANGL2, DVL1, DVL2, DVL3, PRICKLE1, PRICKLE2, ANKRD6, NKD1, NKD2, DAAM1, DAAM2, CELSR1, CELSR2, CELSR3, ROR1 and ROR2 are planar cell polarity (PCP) signaling molecules implicated in the regulation of cellular polarity, convergent extension, and invasion. FAT1, FAT2, FAT3 and FAT4 are Cadherin superfamily members homologous to Drosophila Fat, functioning as a positive regulator of PCP in the Drosophila wing. Complete coding sequence (CDS) for human FAT1 (NM_005245.3) and FAT2 (NM_001447.1) are available, while artificial CDS for human FAT3 (XM_926199 and XM_936538) and partial CDS for FAT4 (NM_024582.2). Here, complete CDS of human FAT3 and FAT4 were determined by using bioinformatics and human intelligence (Humint). FAT3 gene, consisting of 26 exons, encoded a 4557-aa protein with extracellular 33 Cadherin repeats, one Laminin G (LamG) domain and two EGF domains. FAT4 gene encoded a 4924-aa protein with extracellular 34 Cadherin repeats, two LamG domains and three EGF domains. Cytoplasmic VCSVxPxLP and SDYxS motifs were identified as novel motifs conserved among FAT1, FAT2 and FAT3 orthologs. Domain architecture comparison and phylogenetic analysis revealed that FAT1, FAT2 and FAR3 were divergent from FAT4. FAT1-MTNR1A locus at 4q35.2 and FAT3-MTNR1B locus at 11q14.3-q21 were paralogous regions within the human genome. FAT1 mRNA was expressed in embryonic stem (ES) cells, neural tissues, gastric cancer, pancreatic cancer, colorectal cancer, breast cancer, lung cancer and brain tumors. FAT2 mRNA was expressed in infant brain, cerebellum, gastric cancer, pancreatic cancer, ovarian cancer, esophageal cancer, skin squamous cell carcinoma, head and neck cancer. FAT3 mRNA was expressed in ES cells, primitive neuroectoderm, fetal brain, infant brain, adult neural tissues and prostate. FAT4 mRNA was expressed in fetal brain, infant brain, brain tumor and colorectal cancer. FAT family members were revealed to be targets of systems medicine in the fields of oncology and neurology.

Amino Acid Sequence↗

PubMed2006

Hedgehog signaling pathway and gastrointestinal stem cell signaling network (review).

Hedgehog, BMP/TGFbeta, FGF, WNT and Notch signaling pathways constitute the stem cell signaling network, which plays a key role in a variety of processes, such as embryogenesis, maintenance of adult tissue homeostasis, tissue repair during chronic persistent inflammation, and carcinogenesis. Sonic hedgehog (SHH), Indian hedgehog (IHH) and Desert hedgehog (DHH) bind to PTCH1/PTCH or PTCH2 receptor to release Smoothened (SMO) signal transducer from Patched-dependent suppression. SMO then activates STK36 serine/threonine kinase to stabilize GLI family members and to phosphorylate SUFU for nuclear accumulation of GLI. Hedgehog signaling activation leads to GLI-dependent transcriptional activation of target genes, such as GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1. GLI1-dependent positive feedback loop combined with PTCH1-dependent negative feedback loop gives rise to transient proliferation of Hedgehog target cells. Iguana homologs (DZIP1 and DZIP1L) and Costal-2 homologs (KIF7 and KIF27) are identified by comparative integromics. SHH-dependent parietal cell proliferation is implicated in gastric mucosal repair during chronic Helicobacter pylori infection. BMP-RUNX3 signaling induces IHH expression in surface differentiated epithelial cells of stomach and intestine. Hedgehog signals from epithelial cells then induces FOXL1-mediated BMP4 upregulation in mesenchymal cells. Hedgehog signaling is frequently activated in esophageal cancer, gastric cancer and pancreatic cancer due to transcriptional upregulation of Hedgehog ligands and epigenetic silencing of HHIP1/HHIP gene, encoding the Hedgehog inhibitor. However, Hedgehog signaling is rarely activated in colorectal cancer due to negative regulation by the canonical WNT signaling pathway. Hedgehog signaling molecules or targets, such as SHH, IHH, HHIP1, PTCH1 and GLI1, are applied as biomarkers for cancer diagnostics, prognostics and therapeutics. Small-molecule inhibitors for SMO or STK36 are suitable to be used for treatment of Hedgehog-dependent cancer.

Animals↗

PubMed2005

Hedgehog signaling pathway and gastric cancer.

Hedgehog, WNT, FGF and BMP signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. Aberrant activation of Hedgehog signaling pathway leads to pathological consequences in a variety of human tumors, such as gastric cancer and pancreatic cancer. Endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), surgical gastrectomy and chemotherapy are therapeutic options for gastric cancer; however, prognosis of advanced gastric cancer patient is still poor. Here, Hedgehog signaling pathway in human gastric cancer and its clinical applications will be reviewed. Human SHH, IHH, DHH (Hedgehog homologs), HHAT (Hedgehog acyltransferase), HHIP (Hedgehog-interacting protein), DISP1, DISP2, DISP3 (Dispatched homologs), PTCH1, PTCH2 (Patched homologs), SMO (Smoothened homolog), KIF27, KIF7 (Costal-2 homologs), STK36 (Fused homolog), SUFU (SuFu homolog), DZIP1 (Iguana homolog), GLI1, GLI2 and GLI3 (Cubitus interruptus homologs) are implicated in the Hedgehog signaling. PTCH1, FOXM1 and CCND2 are direct transcriptional targets of Hedgehog signaling. Hedgehog signaling activation leads to cell proliferation through cell cycle regulation. SHH regulates growth and differentiation within gastric mucosa through autocrine loop and FOXL1-mediated epithelial-mesenchymal interaction. SHH is implicated in stem/progenitor cell restitution of damaged gastric mucosa during chronic infection with Helicobacter pylori. SHH up-regulation, IHH upregulation and HHIP down-regulation lead to aberrant activation of Hedgehog signaling through PTCH1 to GLI1 in gastric cancer. Small molecule compounds targeted to SMO (KADD-cyclopamine, SANT1-4, Cur61414) as well as humanized anti-SHH antibodies are potent anti-cancer drugs for gastric cancer. Cocktail of Hedgehog inhibitors would be developed as novel therapeutics for gastric cancer. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of Hedgehog signaling genes would be utilized for genetic screening of gastric cancer, while cDNA-PCR, microarray and ELISA detecting aberrant Hedgehog signaling activation would be utilized for therapeutic optional choice. Genetic screening and precise selection of therapeutic options would contribute to the realization of personalized medicine.

Animals↗

PubMed2005

Identification and characterization of rat Desert hedgehog and Indian hedgehog genes in silico.

Sonic hedgehog (SHH), Desert hedgehog (DHH) and Indian hedgehog (IHH) bind to Patched family receptors (PTCH1 and PTCH2) to transduce signals to GLI1, GLI2 and GLI3. GLI family transcription factors then activate transcription of Hedgehog target genes, such as FOXE1 and FOXM1 encoding Forkhead-box transcription factors. Hedgehog signaling pathway plays a pivotal role in a variety of human tumors, such as gastric cancer, pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, basal cell carcinoma and brain tumors. Rat orthologs for human DHH and IHH remain to be identified. Here, we identified and characterized rat Dhh and Ihh genes by using bioinformatics. Rat Dhh complete coding sequence (CDS) was determined by assembling nucleotide positions 426397-426963, 429715-429976 and 430244-430898 of the AC114446.3 genome sequence. Rat Ihh complete CDS was determined by assembling nucleotide positions 63433-64033, 66432-66693 and 68242-69169 of AC095777.6 genome sequence. Rat Dhh mRNA was expressed in prostate, duodenum and dorsal root ganglia, while rat Ihh mRNA was expressed in cartilage. Rat Dhh showed 99.7% total-amino-acid identity with mouse Dhh, and 96.5% total-amino-acid identity with human DHH. Rat Ihh and human IHH were shorter than mouse Ihh by 38 amino acids. Rat Ihh showed 97.6% total-amino-acid identity with mouse Ihh and 94.4% total-amino-acid identity with human IHH. Hedgehog family proteins consist of signal peptide, Hedgehog ligand peptide and C-terminal peptide. Hedgehog ligand peptides derived from mammalian Hedgehog family proteins were conserved well, while C-terminal peptides were relatively divergent. The HPLGMXXXXS motif in the C-terminus was conserved in Shh orthologs and Ihh orthologs, but not in Dhh orthologs.

Amino Acid Motifs↗

PubMed2005

Identification and characterization of DISP3 gene in silico.

Lipid-modified soluble proteins Hedgehog (SHH, DHH and IHH) and WNT (WNT1, WNT2, WNT2B, WNT3, etc.) share distantly related mechanisms for ligand modification as well as for signaling through seven-transmembrane protein with Frizzled domain. Hedgehog and WNT signaling pathways network together during embryogenesis and carcinogenesis. Dispatched 1 (DISP1) and Dispatched 2 (DISP2) are human homologs for Drosophila Dispatched implicated in the release of lipid-anchored Hedgehog from producing cells. Here, we identified and characterized Dispatched 3 (DISP3) gene by using bioinformatics. DISP3 complete coding sequence was determined by assembling BU170953 EST and KIAA1337 uncharacterized cDNA. DISP3 gene at human chromosome 1p36.22 was linked to D1S2667 microsatellite maker and TERE1 gene, whose locus is associated with prostate cancer, bladder cancer, and liver cancer. DISP3 mRNA was expressed in human embryonic stem (ES) cells, brain, testis, lung carcinoid, neuroblastoma, retinoblastoma and brain tumor. DISPH1 domain with five transmembrane regions (codon 452-637 of DISP3) and DISPH2 domain with four transmembrane regions (codon 1116-1319 of DISP3) were identified as novel domains conserved between DISP3 (1392 aa) and DISP1. The region around DISPH1 and DISPH2 domains of DISP3 protein was the Patched homologous region conserved among Patched family members and DISP family members. Because DISP3 and DISP1 are multi-span transmembrane proteins with the Patched homologous region, DISP3 is predicted to be implicated in the release of lipid-anchored secreted proteins. This is the first report on identification and characterization of the DISP3 gene.

Amino Acid Sequence↗

PubMed2005

Identification and characterization of rat Wnt6 and Wnt10a genes in silico.

WNT and Hedgehog signaling pathways are implicated in various types of human cancer, such as gastric and pancreatic cancer. WNT1, WNT2, WNT2B (WNT13), WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A (WNT14), WNT9B (WNT14B). WNT10A, WNT10B, WNT11 and WNT16 genes encode WNT family glycoproteins, which transduce signals through Frizzled (FZD) family receptors with extracellular WNT-binding and cytoplasmic Dishevelled-binding domains. WNT6 and WNT10A genes at human chromosome 2q35 are clustered in tail-to-head manner with an interval of <7 kb. Here, we identified and characterized rat Wnt6 and Wnt10a genes by using bioinformatics. Wnt6 and Wnt10a genes were clustered in tail-to-head manner with an interval of about 7 kb within AC127107.3 and AC132020.3 genome sequences. Rat Wnt6 gene, consisting of four exons, encoded a 365-aa protein with signal peptide, 24 conserved Cys residues, two Asn-linked glycosylation sites and an RGD motif. Rat Wnt10a gene, consisting of four exons, encoded a 417-aa protein with 24 conserved Cys residues, two Asn-linked glycosylation sites and an RGD motif. Rat Wnt6 and human WNT6 showed 97.8% total-amino-acid identity, while rat Wnt10a and human WNT10A showed 95.4% total-amino-acid identity. Promoter region was conserved between rat Wnt6 and human WNT6 genes. GATA, FOXA2, and TGIF binding sites were located within the conserved region of rat Wnt6 and human WNT6 promoters. This is the first report on rat Wnt6 and Wnt10a genes as well as on the conserved promoter region of Wnt6 orthologs.

Amino Acid Sequence↗

PubMed2005

Identification and characterization of rat Bcl9l gene in silico.

Drosophila wingless (wg), shaggy (sgg), armadillo (arm), legless (lgs), pygopus (pygo), pangolin (pan), and engrailed (en) are segment polarity genes implicated in Wg-Arm (WNT-beta-catenin) pathway. Drosophila lgs encodes nuclear scaffold protein functioning as positive regulator for Wg-Arm pathway. Cancer-associated genes BCL9 and BCL9L are human homologs for Drosophila lgs. Here, we identified and characterized rat Bcl9l gene by using bioinformatics. Rat Bcl9l gene, consisting of eight exons, was located within AC124034.4 and AC105645.5 genome sequences. Bcl9l gene was linked to Blr1 gene at rat chromosome 8q22 in the tail-to-tail manner with an interval less than 2 kb. Rat Bcl9l gene was found to encode a 1494-aa Bcl9l protein, which showed 97.7% and 94.2% total-amino-acid identity with mouse Bcl9l and human BCL9L, respectively. B9H1-B9H6 domains, originally identified as conserved regions among mammalian BCL9 and BCL9L homologs, were also identified within rat Bcl9l. B9H1 and B9H2 domains corresponded to HD1 and HD2 domains of Drosophila lgs, functioning as binding regions for Pygo and Arm, respectively. B9H4 domain was characterized by multiple Ser-Pro repeats. Thr 954 within B9H4 domain of rat Bcl9l was conserved in mammalian BCL9 and BCL9L homologs. Phylogenetic analysis revealed that mammalian Bcl9l homologs were more related to human BCL9 than to Drosophila lgs. This is the first report on rat Bcl9l gene.

Amino Acid Sequence↗

PubMed2005

Identification and characterization of rat Wnt1 and Wnt10b genes in silico.

WNT family genes encode WNT family glycoproteins, while Frizzled (FZD) family genes encode seven-transmembrane-type receptors with extracellular WNT-binding domain and cytoplasmic Dishevelled-binding domain. WNT signaling pathway is implicated in carcinogenesis and embryogenesis. WNT1-WNT10B, WNT6-WNT10A, WNT3-WNT9B (WNT14B), WNT3A-WNT9A (WNT14) gene clusters exist within the human genome. Here, we identified and characterized rat Wnt1 and Wnt10b genes by using bioinformatics. Rat Wnt1 gene, consisting of four exons, encoded a 370-aa protein with signal peptide, 22 conserved Cys residues and four Asn-linked glycosylation sites. Rat Wnt10b gene, consisting of five exons, encoded a 389-aa protein with signal peptide, 24 conserved Cys residues and two Asn-linked glycosylation sites. Wnt1 and Wnt10b genes at rat chromosome 7q36 were clustered in head-to-head manner with an interval of about 10 kb within AC096835.4 or AC118760.4 genome sequences. Promoter region, exon 1 and 5'-part of intron 1 were conserved between rat and human Wnt1 orthologs. Intergenic conserved region (IGCR) was identified within the Wnt1-Wnt10b gene cluster. GC content of rat Wnt1-Wnt10b IGCR (nucleotide position 14962-15875 of AC096835.4 genome sequence) was 59.4%. Rat Wnt1-Wnt10b IGCR showed 92.5 and 74.4% nucleotide identity with mouse Wnt1-Wnt10b IGCR and human WNT1-WNT10B IGCR, respectively. Wnt1-Wnt10b IGCR was predicted as regulatory element rather than gene because cDNA or EST derived from Wnt1-Wnt10b IGCR was not identified. This is the first report on rat Wnt1 and Wnt10b genes as well as on Wnt1-Wnt10b IGCR.

Amino Acid Sequence↗

PubMed2005

Comparative genomics on Wnt16 orthologs.

The WNT16 gene at human chromosome 7q31.31 encodes two isoforms due to alternative splicing of an alternative promoter type. Here, we identified and characterized the rat Wnt16 and zebrafish wnt16 genes using bioinformatics. The rat Wnt16 and zebrafish wnt16 genes, consisting of four exons, were located within the AC117014.4 and CR925699.1 genome sequences, respectively. Exons 1b, 2, 3 and 4 of the human WNT16 gene were conserved in the rodent Wnt16 and zebrafish wnt16 genes; however, exon 1a of the human WNT16 gene was not conserved. Human WNT16 isoform 1 (NM_057168.1), consisting of exons 1b, 2, 3 and 4, was identified as the evolutionarily conserved representative isoform. Because zebrafish NM_207096.1 was an aberrant wnt16 cDNA with a retained 3'-part intron 1, complete CDS of representative zebrafish wnt16 was determined by deleting nucleotide position 183-239 from NM_207096.1 aberrant cDNA. Rat Wnt16 (364 aa) with an N-terminal signal peptide, 24 Cys residues and 3 Asn-linked glycosylation sites showed 97.3, 90.4 and 65.9% total-amino-acid identity with mouse Wnt16, human WNT16, and zebrafish wnt16, respectively. Phylogenetic analyses on WNT family members revealed that WNT16 was most closely related to WNT7A and WNT7B paralogs. Promoters of human WNT16, rat Wnt16 and mouse Wnt16 genes were well conserved. Double CCAAT motifs were conserved among mammalian Wnt16 promoters. This is the first report on the rat Wnt16 and zebrafish wnt16 genes, as well as the double CCAAT motifs within the core promoter regions of mammalian Wnt16 orthologs.

Amino Acid Motifs↗

PubMed2005

Comparative genomics on Wnt11 gene.

Non-canonical WNTs activate the planar cell polarity (PCP) pathway to induce cell motility and metastasis, while canonical WNTs activate the beta-catenin-TCF pathway to induce carcinogenesis. WNT11 gene at human chromosome 11q13.5 encodes non-canonical WNT11 protein, which is applicable for regenerative medicine of heart diseases. Here, we identified and characterized rat Wnt11 gene by using bioinformatics. Rat Wnt11 gene, consisting of five exons, was identified within AC120107.3 genome sequence. Rat Wnt11 (354 aa) was a secreted protein with 24 conserved Cys residues and five Asn-linked glycosylation sites. Rat Wnt11 showed 99.4%, 97.5%, 84.5% and 76.0% total-amino-acid identity with mouse Wnt11, human WNT11, chicken wnt11 and zebrafish wnt11, respectively. Comparative proteomics revealed that the number of Asn-linked glycosylation sites increased during molecular evolution of Wnt11 orthologs. Comparative genomics revealed that exon 1, but not 5'-flanking region, was well conserved between rat Wnt11 and human WNT11 genes. Although conserved transcription-factor-binding site was not identified within 5'-flanking region of rat Wnt11 and human WNT11 genes, Nkx2-5-binding site within exon 1 was evolutionarily conserved among mammalian Wnt11 orthologs. Because Nkx2-5 and Wnt11 are key regulators of heart development, Wnt11 was predicted as a target gene of Nkx2-5 transcription factor during cardiac myocyte differentiation. This is the first report on rat Wnt11 gene as well as on comparative genomics for Wnt11 orthologs.

5' Flanking Region↗