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Masuko Katoh

Publications and source records attributed to Masuko Katoh.

At least 19 recordsLinked to original sources
PubMed2007

Notch signaling in gastrointestinal tract (review).

Notch signaling is one of key pathways constituting the stem cell signaling network. DLL1, DLL3, DLL4, JAG1 and JAG2 with DSL domain are typical Notch ligands, while DNER, F3/Contactin and NB-3 without DSL domain are atypical Notch ligands. Notch-ligand binding to NOTCH1, NOTCH2, NOTCH3 or NOTCH4 receptor induces the receptor proteolysis by metalloprotease and gamma-secretase to release Notch intracellular domain (NICD). Typical Notch ligands transduce signals to the CSL-NICD-Mastermind complex for the maintenance of stem or progenitor (transit-amplifying) cells through transcriptional activation of HES1, HES5, HES7, HEY1, HEY2 and HEYL genes, and also to the NF-kappaB-NICD complex for the augmentation of NF-kappaB signaling. Atypical Notch ligands transduce signals to the CSL-NICD-Deltex complex for the differentiation of progenitor cells through MAG transcriptional activation. Notch signals are transduced to the canonical pathway (CSL-NICD-Mastermind signaling cascade) or the non-canonical pathway (NF-kappaB-NICD and CSL-NICD-Deltex signaling cascades) based on the expression profile of Notch ligands, Notch receptors, and Notch signaling modifiers. Canonical Notch signaling is activated in the stem or progenitor domain of gastrointestinal epithelium, such as basal layer in esophagus and lower part of the crypt in colon. Notch signaling to inhibit secretory cell differentiation is oncogenic in gastric cancer and colorectal cancer, while Notch signaling to promote keratinocyte differentiation is anti-oncogenic in esophageal squamous cell carcinoma (SCC). Single nucleotide polymorphism (SNP), epigenetic change, and genetic alteration of genes encoding Notch signaling-associated molecules will be utilized as biomarkers for gastrointestinal cancer. gamma-Secretase inhibitors, functioning as Notch signaling inhibitors, will be applied as anti-cancer drugs for gastric cancer and colorectal cancer.

Gastrointestinal Neoplasms↗
PubMed2007

WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates.

Notch and WNT signaling pathways are key components of the stem cell signaling network. Canonical WNT signaling to intestinal progenitor cells leads to transcriptional activation of the JAG1 gene, encoding Serrate-type Notch ligand. JAG1 then binds to the Notch receptor on adjacent stem cells to induce Notch receptor proteolyses for the release of Notch intracellular domain (NICD). NICD is associated with CSL/RBPSUH and Mastermind (MAML1, MAML2, or MAML3) to activate Notch target genes, such as HES1 and HES5. Although WNT-dependent Notch signaling activation in intestinal stem cells is clarified, the effects of Notch signaling activation on WNT signaling in progenitor cells remain unclear. We searched for Notch-response element (NRE) in the promoter region of genes encoding secreted WNT signaling inhibitors, including DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 and WIF1. Double NREs were identified within human DKK2 promoter by bioinformatics and human intelligence (Humint). The human DKK2 gene was characterized as Notch signaling target in intestinal stem cells. Because DKK2 is a key player in the stem cell signaling network, the DKK2 gene at human chromosome 4q25 is a candidate tumor suppressor gene inactivated due to epigenetic silencing and/or deletion. The chimpanzee DKK2 gene was identified within the NW_105990.1 genome sequence, while the cow Dkk2 gene was identified within the AC156664.2 and AC158038.2 genome sequences. Chimpanzee DKK2 and cow Dkk2 showed 98.5% and 95.8% total-amino-acid identity with human DKK2, respectively. Double NREs in human DKK2 promoter were conserved in chimpanzee DKK2 promoter, partially in rat Dkk2 promoter, but not in cow and mouse Dkk2 promoters. The Notch-DKK2 signaling loop, created or potentiated in primates, was complementary to WNT-DKK1 and BMP-IHH-SFRP1 signaling loops for negative regulation of canonical WNT signaling pathway. Together, these facts indicate that DKK2 promoter evolution resulted in the augmentation of a WNT negative regulation system in primates.

Amino Acid Sequence↗
PubMed2007

STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer (Review).

Leukemia inhibitory factor (LIF), oncostatin M, leptin, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine factor 1, interleukin 6 (IL6), interleukin 11 and interleukin 27 activate the gp130-JAK-STAT3 signaling cascade. Here, WNT5A was characterized as the evolutionarily conserved target of the STAT3 signaling cascade based on 11-bp-spaced tandem STAT3-binding sites within intron 4 of human, chimpanzee, cow, mouse and rat WNT5A orthologs. Canonical WNT5A signaling through Frizzled and LRP5/LRP6 receptors activates FGF20, WISP1, MYC and CCND1 transcription for the maintenance of stem/progenitor cells, while non-canonical WNT5A signaling through Frizzled and ROR2/PTK7/RYK receptors activates the RHOA, JNK, NLK and NFAT signaling cascades for the control of tissue polarity, cell adhesion or movement. LIF-induced Wnt5a activates canonical Wnt signaling in mouse embryonic stem cells for self-renewal. STAT3-induced Wnt5a activates non-canonical Wnt signaling in rat cardiac myocytes for N-cadherin-dependent aggregation. IL6, secreted from epithelial cells or macrophages, induces WNT5A upregulation in mesenchymal cells. WNT5A then activates canonical WNT signaling in epithelial cells. IL6-induced WNT5A activates canonical WNT signaling for autocrine proliferation of human synovial fibroblasts in rheumatoid arthritis. IL-6 signaling is activated during human chronic atrophic gastritis with Helicobacter pylori infection, and aberrant Stat3 signaling activation gives rise to mouse gastric tumors. WNT5A is frequently upregulated in human primary gastric cancer due to tumor-stromal interaction. WNT5A might be downregulated in advanced cancer with poorer prognosis due to genetic alterations compensating WNT5A signaling. Oncogenic WNT5A activates canonical WNT signaling in cancer stem cells for self-renewal, and non-canonical WNT signaling at the tumor-stromal interface for invasion and metastasis. SNP of genes encoding components of the cytokine-induced WNT5A signaling loop is a predicted risk factor for RA and cancer, especially diffuse-type gastric and pancreatic cancer. Humanized anti-IL6 receptor antibody and WNT5A mimetic small-molecule antagonist could be applied to personalized medicine for RA and cancer driven by the IL6-induced WNT5A signaling loop.

Animals↗
PubMed2006

Cross-talk of WNT and FGF signaling pathways at GSK3beta to regulate beta-catenin and SNAIL signaling cascades.

WNT and FGF signaling pathways cross-talk during a variety of cellular processes, such as human colorectal carcinogenesis, mouse mammary tumor virus (MMTV)-induced carcinogenesis, E2A-Pbx-induced leukemogenesis, early embryogenesis, body-axis formation, limb-bud formation, and neurogenesis. Canonical WNT signals are transduced through Frizzled receptor and LRP5/6 coreceptor to downregulate GSK3beta (GSK3B) activity not depending on Ser 9 phosphorylation. FGF signals are transduced through FGF receptor to the FRS2-GRB2-GAB1-PI3K-AKT signaling cascade to downregulate GSK3beta activity depending on Ser 9 phosphorylation. Because GSK3beta-dependent phosphorylation of beta-catenin and SNAIL leads to FBXW1 (betaTRCP)-mediated ubiquitination and degradation, GSK3beta downregulation results in the stabilization and the nuclear accumulation of beta-catenin and SNAIL. Nuclear beta-catenin is complexed with TCF/LEF, Legless (BCL9 or BCL9L) and PYGO (PYGO1 or PYGO2) to activate transcription of CCND1, MYC, FGF18 and FGF20 genes for the cell-fate determination. Nuclear SNAIL represses transcription of CDH1 gene, encoding E-cadherin, to induce the epithelial-mesenchymal transition (EMT). Mammary carcinogenesis in MMTV-Wnt1 transgenic mice is accelerated by MMTV infection due to MMTV integration around Fgf3-Fgf4 or Fgf8 loci, and mammary carcinogenesis in MMTV-Fgf3 transgenic mice due to MMTV integration around Wnt1-Wnt10b locus. Coactivation of WNT and FGF signaling pathways in tumors leads to more malignant phenotypes. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of WNT and FGF signaling molecules could be utilized as screening method of cancer predisposition. cDNA-PCR, microarray or ELISA reflecting aberrant activation of WNT and FGF signaling pathways could be developed as novel cancer-related biomarkers for diagnosis, prognosis, and therapy. Cocktail therapy using WNT and FGF inhibitors, such as small-molecule compounds and human neutralizing antibodies, should be developed to increase the efficacy of chemotherapy through the inhibition of recurrence by destructing cancer stem cells.

Animals↗
PubMed2006

Bioinformatics for cancer management in the post-genome era.

Human cancer is caused by multiple factors, such as genetic predisposition, chronic persistent inflammation, environmental factors, life style, and aging. Dysregulated proliferation, dysregulated adhesion, resistance to apoptosis, resistance to senescence, and resistance to anti-cancer drugs are features of cancer cells. Accumulation of multiple epigenetic changes and genetic alterations of cancer-associated genes during multi-stage carcinogenesis results in more malignant phenotypes. Post-genome science is characterized by omics data related to genome, transcriptome, proteome, metabolome, interactome, and epigenome as well as by high-throughput technology, such as whole-genome tiling oligonucleotide array, array CGH with 32,433 overlapping BAC clones, transcriptome microarray, mass spectrometry, tissue-based expression array, and cell-based transfection array. Benchtop oncology supplies Desktop oncology with large amounts of omics data produced by high-throughput technology. Desktop oncology establishes knowledge on cancer-related biomarkers, such as predisposition markers, diagnostic markers, prognostic markers, and therapeutic markers, by using bioinformatics and human intelligence of experts for data mining and text mining. Bedside oncology applies the knowledge established by Desktop oncology to determine therapeutics for cancer patients. Antibody drugs (Trastuzumab/Herceptin, Cetuximab/Erbitux, Bevacizumab/Avastin, et cetera), small molecule inhibitors for tyrosine kinases (Gefitinib/Iressa, Erlotinib/Tarceva, Imatinib/Gleevec, et cetera), conventional cytotoxic drugs, and anti-hormonal drugs are used for cancer chemotherapy. Biomarker monitoring contributes to therapeutic optional choice and drug dosage determination for cancer patients. Knowledge on biomarkers is feedforwarded from desktop to bedside in the translational research, and then biomarker monitoring is feedbacked from bedside to desktop in the reverse translational research. Desktop oncology is indispensable for cancer research in the post-genome era. Combination of genetic screening for cancer predisposition in the general population and precise selection of therapeutic options during cancer management could contribute to the realization of personalized prevention and to dramatically improve the prognosis of cancer patients in the future.

Antineoplastic Agents↗
PubMed2006

Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells.

WNT, Notch, FGF, and Hedgehog signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. Association of Notch ligands with Notch receptors on neighboring cells leads to cleavage of Notch receptors by metalloprotease and gamma-secretase to induce nuclear translocation of Notch intracellular domain (NICD). Nuclear complex, consisting of CSL (RBPSUH), NICD, Mastermind (MAML), p300 and histone acetyltransferase (HAT), then induces transcriptional activation of Notch target genes, such as HES1, HES5, HES7, HEY1, HEY2 and HEYL. Here, we searched for TCF/LEF-binding site within the promoter region of Notch ligand genes, including DLL1, DLL3, DLL4, JAG1 and JAG2. Because TCF/LEF-binding sites were identified within human JAG1 promoter based on bioinformatics and human intelligence, comparative genomics analyses on JAG1 orthologs were further performed. Chimpanzee JAG1 gene, consisting of 26 exons, was identified within NW_120319.1 genome sequence. XM_525264.1 and XM_514517.1 were not the correct coding sequences for chimpanzee JAG1. Chimpanzee JAG1 gene was found to encode a 1218-amino-acid protein showing 99.5% and 96.2% total-amino-acid identity with human JAG1 and mouse Jag1, respectively. Phylogenetic analysis revealed that JAG1 orthologs were more conserved than those of other Notch ligands. JAG1 gene was identified as 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 JAG1 orthologs. Human JAG1 mRNA was expressed in embryonic stem (ES) cells, neural tissues, lung carcinoid, gastric cancer, pancreatic cancer, colon cancer, and also in squamous cell carcinoma (SCC) of skin, oral cavity, esophagus, head and neck. JAG1 expression on progenitor cells due to canonical WNT signaling activation induces self-renewal of stem cells due to Notch signaling activation. JAG1, functioning as WNT-dependent Notch signaling activator, is the key molecule maintaining the homeostasis of stem and progenitor cells.

Amino Acid Sequence↗
PubMed2006

Comparative integromics on Eph family.

EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4 and EPHB6 are EPH family receptors for Ephrin family ligands. Ephrin/EPH signaling pathway networks with the WNT signaling pathway during embryogenesis, tissue regeneration, and carcinogenesis. TCF/LEF-binding sites within the promoter region of human EPH family members were searched for by using bioinformatics and human intelligence. Because five TCF/LEF-binding sites were identified within the 5'-promoter region of the EPHA7 gene, comparative genomics analyses on EPHA7 orthologs were further performed. EPHA7-MANEA-FHL5 locus at human chromosome 6q16.1 and EPHA10-MANEAL-FHL3 locus at human chromosome 1p34.3 were paralogous regions within the human genome. Human EPHA7 mRNA was expressed in embryonic stem (ES) cells, neural tissues, duodenal cancer and parathyroid tumors, while mouse Epha7 mRNA was expressed in fertilized egg, Rathke's pouche, visual cortex, pituitary gland, other neural tissues, pancreas, lung tumors and mammary tumors. The chimpanzee EPHA7 gene and cow Epha7 gene were identified within NW_107969.1 and AC155055.2 genome sequences, respectively. Five TCF/LEF-binding sites within human EPHA7 promoter were conserved in the chimpanzee EPHA7 promoter, and three TCF/LEF-binding sites in the cow Epha7 promoter, but none in the mouse Epha7 promoter. Primates and cow EPHA7 orthologs were identified as evolutionarily conserved targets of the WNT/beta-catenin signaling pathway. D6S1056 microsatellite marker within EPHA7 gene is deleted in prostate cancer. Deletion and/or promoter CpG hypermethylation could explain the EPHA7 down-regulation in human tumors. EPHA7 is a target of systems medicine, especially in the fields of regenerative medicine and oncology.

Animals↗
PubMed2006

CER1 is a common target of WNT and NODAL signaling pathways in human embryonic stem cells.

Nodal and BMP signaling pathways network with WNT signaling pathway during embryogenesis and carcinogenesis. CER1 (Cerberus 1) and GREM3 (CKTSF1B3 or CER2) inhibit NODAL signaling through ACVR1B (ALK4) or ACVR1C (ALK7) to SMAD2 or SMAD3. GREM1 (CKTSF1B1) inhibits BMP signaling through BMPR1A (ALK3), BMPR1B (ALK6) or ACVR1 (ALK2) to SMAD1, SMAD5 or SMAD8. CER1, GREM1 and GREM3 are DAN domain (DAND) family members; however, transcriptional regulation of DAND family members by canonical WNT signaling pathway remains unclear. We searched for the TCF/LEF-binding site within the promoter region of DAND family genes, including CER1, GREM1, GREM2, GREM3 and NBL1. Because triple TCF/LEF-binding sites were identified within human CER1 promoter by using bioinformatics and human intelligence, comparative genomics analyses on CER1 orthologs were further performed. Chimpanzee CER1 gene, encoding 267-amino-acid protein, was identified within NW_111298.1 genome sequence. XM_528542.1 was not a correct coding sequence for chimpanzee CER1. Primate CER1 orthologs were significantly divergent from rodent Cer1 orthologs. Three TCF/LEF-binding sites within human CER1 promoter were conserved in chimpanzee CER1 promoter, two in cow and dog Cer1 promoters, but not in rodent Cer1 promoters. Binding sites for NODAL signaling effectors, SMAD3/SMAD4 and FOXH1, were also conserved among human, chimpanzee, cow and dog CER1 promoters. CER1 orthologs were evolutionarily conserved target of WNT and NODAL signaling pathways in non-rodent mammals. Human CER1 mRNA was expressed in embryonic stem (ES) cells in the undifferentiated state and in the early endodermal lineage. CER1 upregulation in human ES cells leads to Nodal signaling inhibition associated with differentiation of human ES cells. Primate CER1 orthologs, playing a pivotal role during early embryogenesis, underwent protein evolution as well as promoter evolution. These facts indicate that molecular evolution of CER1 orthologs contributes to the significantly divergent scenarios of early embryogenesis in primates and rodents.

Amino Acid Sequence↗
PubMed2006

FGF signaling network in the gastrointestinal tract (review).

Fibroblast growth factor (FGF) signals are transduced through FGF receptors (FGFRs) and FRS2/FRS3- SHP2 (PTPN11)-GRB2 docking protein complex to SOS-RAS-RAF-MAPKK-MAPK signaling cascade and GAB1/GAB2-PI3K-PDK-AKT/aPKC signaling cascade. The RAS approximately MAPK signaling cascade is implicated in cell growth and differentiation, the PI3K approximately AKT signaling cascade in cell survival and cell fate determination, and the PI3K approximately aPKC signaling cascade in cell polarity control. FGF18, FGF20 and SPRY4 are potent targets of the canonical WNT signaling pathway in the gastrointestinal tract. SPRY4 is the FGF signaling inhibitor functioning as negative feedback apparatus for the WNT/FGF-dependent epithelial proliferation. Recombinant FGF7 and FGF20 proteins are applicable for treatment of chemotherapy/radiation-induced mucosal injury, while recombinant FGF2 protein and FGF4 expression vector are applicable for therapeutic angiogenesis. Helicobacter pylori, a causative pathogen for peptic ulcer diseases, chronic atrophic gastritis and gastric cancer, injects bacterial proteins into gastric epithelial cells by using Type IV secretion system, which leads to FGF signaling activation through FGF2 upregulation as well as CagA-dependent SHP2 activation. FGFR2 gene is preferentially amplified and overexpressed in diffuse-type gastric cancer. PD173074 is a small-molecule inhibitor for FGFR, while RO4396686 and SU6668 are small-molecule inhibitors for FGFR and other tyrosine kinases. Cocktail therapy using multiple protein kinase inhibitors could enhance the therapeutic effects for gastrointestinal cancer through the reduction of recurrence associated with somatic mutations of drug-target genes. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of genes encoding FGF signaling molecules will be identified as novel risk factors of gastrointestinal cancer. Personalized prevention and personalized medicine based on the combination of genetic screening and novel therapeutic agents could dramatically improve the prognosis of cancer patients.

Amino Acid Sequence↗
PubMed2006

NUMB is a break of WNT-Notch signaling cycle.

Notch, FGF and WNT signaling pathways cross-talk during embryogenesis, tissue regeneration and carcinogenesis. Notch-ligand binding to Notch receptors leads to the cleavage of Notch receptors and the following nuclear translocation of Notch intracellular domain (NICD) to induce transcriptional activation of Notch target genes. Notch signaling inhibitors, NUMB and NUMB-like (NUMBL), are docking proteins with PTB domain. We searched for the TCF/LEF-binding site within the promoter region of NUMB and NUMBL genes. Because two TCF/LEF-binding sites were identified within human NUMB promoter based on bioinformatics and human intelligence (Humint), comparative integromics analyses on NUMB orthologs were further performed. Chimpanzee NUBM gene, consisting of 13 exons, was identified within NW_115880.1 genome sequence. XM_510045.1 was not the correct coding sequence for chimpanzee NUMB. Chimpanzee NUMB gene was found to encode a 651-amino-acid protein showing 99.5, 93.9 and 82.6% total-amino-acid identity with human NUMB, mouse Numb and chicken numb, respectively. Human NUMB mRNA was expressed in placenta, ES cells, neural tissues, trachea, testis, uterus, thymus, coronary artery as well as in a variety of tumors, such as cervical cancer, tong tumor, brain tumor, colorectal and breast cancer. Although distal TCF/LEF-binding site within human NUMB promoter was conserved only among primate NUMB orthologs, proximal TCF/LEF-binding site was conserved among primate and rodent NUMB orthologs. NUMB, JAG1, FGF18, FGF20 and SPRY4 are potent targets of the canonical WNT signaling pathway in progenitor cells. NUMB inhibits Notch signaling in progenitor cells to induce differentiation, while JAG1 activates Notch signaling in stem cells to maintain self-renewal potential. Because Notch signaling inhibitor NUMB was identified as the safe apparatus for the WNT - Notch signaling cycle, epigenetic silencing, deletion and loss-of-function mutation of NUMB gene could lead to carcinogenesis through the dysregulation of the WNT - Notch signaling cycle.

Animals↗
PubMed2005

Comparative genomics on ROR1 and ROR2 orthologs.

Transmembrane proteins with extracellular Frizzled domain, such as ROR1, ROR2, MUSK, MFRP, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9 and FZD10, are key molecules for WNT signaling network. Here, comparative integromics analyses on ROR1 and ROR2 orthologs were performed by using bioinformatics. Zebrafish ror2 gene, consisting of nine exons, was identified within CR-450684.3 genome sequence. CV490605.1 EST corresponded to the 5'-end of zebrafish ror2 mRNA, and BM533602.1 EST corresponded to the 3'-end. Zebrafish ror2 gene was found to encode a 939-aa transmembrane protein, showing 71.7% and 56.2% total amino-acid identity with human ROR2 and ROR1, respectively. Immunoglobulin-like domain, Frizzled domain, Kringle domain within the extracellular region, tyrosine kinase domain, Ror homology C-terminal (RORHC) domain and juxta-C-terminal LLGD motif within the cytoplasmic region were conserved among vertebrate ROR1 and ROR2 orthologs. SH2 binding site within the RORHC domain was conserved among vertebrate ROR2 orthologs, but not among vertebrate ROR1 orthologs. ROR1 mRNA was expressed in embryonic stem (ES) cells, infant brain, renal cancer, and colon cancer. ROR2 mRNA was expressed in parathyroid, testis, uterus, and also in diffuse type gastric cancer with signet ring cell features. ROR2 promoter rather than ROR1 promoter was more evolutionarily conserved. WNT5A and ROR family receptors, co-expressed in ES cells and gastric cancer, are implicated in the planar cell polarity (PCP) pathway. ROR1 and ROR2 are the pharmacogenomics targets in the fields of stem cell biology and oncology.

Amino Acid Sequence↗
PubMed2005

Characterization of KIF12 gene in silico.

Kinesin family (KIF) proteins with Kinesin motor catalytic (KISc) domain and Coiled-coil domain are micro-tubule-dependent molecular motors. KIF proteins produce forces by using the energy from ATP hydrolysis within the KISc domain. We have recently identified that KIF27 is one of mammalian orthologs for Drosophila Costal-2 (Cos2), functioning as regulator of Hedgehog signaling pathway. Mouse Kif12 RefSeq (NM_010616.1) contains the complete coding sequence (CDS); however, human KIF12 Refseq (NM_138424.1) encodes an N-terminally truncated KIF12 protein corresponding to codon 134-642 of mouse Kif12. Here, we characterized the human KIF12 gene by using bioinformatics. Complete CDS of human KIF12 was determined by assembling nucleotide sequences of BQ129377.1 EST, CD358781.1 EST and NM_138424.1 RefSeq. KIF12 gene at human chromosome 9q32 consists of 19 exons. NM_138424.1 RefSeq was a variant KIF12 cDNA with alternative transcription start site (TSS) and skipping of exon 4. NM_138424.1 RefSeq encoded a 513-amino-acid aberrant KIF7 protein with N-terminal-truncation, while KIF12 complete CDS encoded a 651-amino-acid full-length KIF12 protein. Representative human KIF12 and mouse Kif12 proteins with 80.8% total-amino-acid identity shared the common domain architecture, consisting of KISc domain, Coiled-coil domain with internal hinge region, and C-terminal tail domain. KIF12 mRNA was expressed in fetal liver, adult brain and pancreatic islet as well as in kidney tumors, uterus cancer and pancreatic cancer. This is the first report on comprehensive characterization of the human KIF12 gene.

Amino Acid Sequence↗
PubMed2005

Identification and characterization of TMEM16H gene in silico.

TMEM16A gene is located within the CCND1-ORAOV1-FGF19-FGF4-FGF3-TMEM16A-FADD-PPFIA1-CTTN (cortactin or EMS1) amplicon at human chromosome 11q13.3. TMEM16A, TMEM16B, TMEM16C, TMEM16D, TMEM16E (GDD1), TMEM16F, TMEM16G and TP53I5 are TMEM16 family proteins with TM16H1, TM16H2 and TM16H3 domains. Here, we identified and characterized TMEM16H gene by using bioinformatics. Human TMEM16H gene, consisting of 18 exons, was located at human chromosome 19p13.11. AB046843.2 cDNA corresponded to TMEM16H isoform 1 without intron 17, while CR616031.1 cDNA corresponded to TMEM16H isoform 2 with retained intron 17. TMEM16H isoforms were eight-transmembrane proteins with TM16H3 domain. The last exon of isoforms 1 and 2 corresponded to C-terminal 122 and 227 aa, respectively. Human TMEM16H isoform 1 was the major transcript, while isoform 2 was the minor transcript prone to non-sense mediated mRNA decay (NMD). TMEM16H mRNA was expressed in embryonic stem (ES) cells, fetal brain, and neural tissues. Mouse Tmem16h representative cDNA was determined by assembling BC027735.1 and BC059855.1 cDNAs. Mouse and rat Tmem16h genes encoded Tmem16h proteins similar to human TMEM16H isoform 2. The regions corresponding to exons 17 and 18 of human TMEM16H gene were not separated by intron within mouse and rat Tmem16h genes. Insertion of intron 17 into human TMEM16H gene during evolution resulted in the generation of TMEM16H isoform 1. This is the first report on identification and characterization of the TMEM16H gene as well as on the molecular evolution of TMEM16H.

Amino Acid Sequence↗
PubMed2005

Identification and characterization of rat Ankrd6 gene in silico.

WNT signals are transduced to the beta-catenin pathway or the planar cell polarity (PCP) pathway. Drosophila Frizzled (Fz), Starry night (Stan), Van Gogh (Vang), Prickle (Pk) and Diego (Dgo) are PCP signaling molecules. Human FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9 and FZD10 are Fz homologs. Human CELSR1, CELSR2 and CELSR3 are Stan homologs. Human VANGL1 and VANGL2 are Vang homologs. Human PRICKLE1 and PRICKLE2 are Pk homologs. Human ANKRN6 is a Dgo homolog. Here, we identified and characterized rat Ankrd6 gene by using bioinformatics. Ankrd6 gene, consisting of 15 exons, was located within AC105547.5 genome sequence derived from rat chromosome 5q21. Rat Ankrd6 mRNA was expressed in corpus-striatum, eye, lung, and kidney. Rat Ankrd6 (714 aa) with six ankyrin (Ank) repeats and two coiled-coil regions showed 95.0, 84.2 and 53.4% total-amino-acid identity with mouse, human and zebrafish orthologs, respectively. Ser 340 of rat Ankrd6, conserved among mammalian Ankrd6 orthologs, was a protein kinase A (PKA) phosphotylation and 14-3-3 interaction site. Ank repeats are putative binding domains for Prickle1, Prickle2, Vangl1, and Vangl2. Central coiled-coil region is located within binding domain for Casein kinase I epsilon (CkIe). C-terminal coiled-coil region is located within binding domain for Axin1 and Axin2. Fourth to sixth Ank repeats of vertebrate Ankrd6 orthologs (codon 141-239) were highly conserved in Drosophila Dgo; however, two coiled-coil regions of vertebrate Ankrd6 orthologs were absent in Drosophila Dgo. Due to the molecular evolution, functions of vertebrate Ankrd6 orthologs were predicted to partially differ from those of Drosophila Dgo.

14-3-3 Proteins↗
PubMed2005

Identification and characterization of rat Ror1 and Ror2 genes in silico.

Frizzled-1 (FZD1), FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9 and FZD10 are seven-transmembrane-type WNT receptors with extracellular Frizzled (Fz) domain. ROR1, ROR2 and MUSK are receptor-type tyrosine kinases with extracellular Fz domain, while MFRP is type II transmembrane protein with extracellular Fz domain. ROR1, ROR2, MUSK and MFRP are predicted to transduce or regulate WNT signaling. Here, we identified and characterized rat Ror1 and Ror2 genes by using bioinformatics. Rat Ror1 gene was located within AC108320.4, AC098031.5 and AC129856.4 genome sequences, while rat Ror2 gene was located within AC139870.3 and AC123431.4 genome sequences. Exon-intron structure was conserved between rat Ror1 and Ror2 genes, consisting of nine exons. Rat Ror1 mRNA was expressed in fetal ventricle, while rat Ror2 mRNA was expressed in cerebral cortex, hypothalamus, dorsolateral prostate, and chondrosarcoma. Rat Ror1 (937 aa) and Ror2 (943 aa) showed 56.5% total-amino-acid identity. Rat Ror1 and Ror2 were type I transmembrane proteins with extracellular Immunoglobulin-like (Ig), Fz, Kringle (KR) domains, and cytoplasmic Juxta-membrane (JM), Tyrosine kinase (TK), and Ror homology C-terminal (RORHC) domains. Casein kinase Iepsilon-binding RORHC domain was conserved among vertebrate Ror1 and Ror2 homologs, but not in Drosophila Ror. Thr 582 within TK domain was conserved among mammalian Ror family members, and was predicted as Casein kinase I phosphorylation site. This is the first report on rat Ror1 and Ror2 genes as well as on molecular evolution of Ror1 and Ror2 homologs.

Amino Acid Sequence↗
PubMed2005

Comparative genomics on Wnt8a and Wnt8b genes.

WNT family ligands transduce signals through FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD9, FZD10, LRP5, LRP6, ROR1, ROR2 and RYK. WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT8A, WNT8B, WNT10A and WNT10B are canonical WNTs to activate WNT - beta-catenin pathway. Human WNT8A mRNA is expressed in NT2 cells with neuronal differentiation potential, while human WNT8B mRNA in diffuse type gastric cancer. Here, we identified and characterized the rat Wnt8a and Wnt8b genes by using bioinformatics. The rat Wnt8a gene, consisting of six exons, was located within AC134361.2 genome sequence. The rat Wnt8b gene, consisting of six exons, was located within AC105487.6 and AC103018.7 genome sequences. The rat Wnt8a (355 aa) and Wnt8b (350 aa) with 60.0% total-amino-acid identity were secreted-type proteins with 22 conserved Cys residues and two Asn-linked glycosylation sites. Wnt8b orthologs were more conserved than Wnt8a orthologs. GATA-binding site was located within conserved region of rat Wnt8b and human WNT8B promoters. GATA6 ESTs were expressed in diffuse type gastric cancer, and FGFR2 gene is reported preferentially amplified in diffuse type gastric cancer. KGF-FGFR2-PI3K-GATA6-WNT8B signaling cascade is predicted to play important roles in diffuse type gastric cancer. This is the first report on the rat Wnt8a and Wnt8b genes as well as on the conserved GATA-binding site within rat Wnt8b and human WNT8B promoters.

Amino Acid Sequence↗
PubMed2005

Comparative genomics on Wnt5a and Wnt5b genes.

Canonical WNTs (WNT2, WNT2B, etc) activate the beta-catenin-TCF pathway to induce carcinogenesis, while non-canonical WNTs (WNT5A, WNT11, etc) activate the planar cell polarity (PCP) pathway to induce cell motility and metastasis. WNT5A gene at chromosome 3p14.3 and WNT5B gene at chromosome 12p13.33 are paralogs within the human genome. Here, we identified and characterized rat Wnt5a and Wnt5b genes by using bioinformatics. Rat Wnt5a and Wnt5b genes, consisting of five exons, were identified within AC095764.5 and AC112027.3 genome sequences, respectively. Rat Wnt5a (380 aa) and Wnt5b (359 aa) were secreted proteins with 24 conserved Cys residues and four Asn-linked glycosylation sites, which showed 75.8% total-amino-acid identity. Nucleotide position 182586-183836 of AC095764.5 genome sequence and nucleotide position 161044-159886 of AC121764.2 genome sequence were identified as evolutionarily conserved rat Wnt5a and human WNT5A promoters, respectively. Nucleotide identity between rat Wnt5a and human WNT5A promoters was 72.5%. E47 and NKX2-5-binding sites were evolutionarily conserved among rat Wnt5a, mouse Wnt5a, and human WNT5A promoters. On the other hand, rodent Wnt5b promoters and human WNT5B promoter were significantly divergent. Up-regulation of Wnt5b during rodent adipocytic differentiation does not simply indicate the implication of WNT5B in human adipogenesis. Real susceptibility gene for type 2 diabetes, associated with SNP within intron 3 of human WNT5B gene (IMS-JST024404), remains to be identified. This is the first report on rat Wnt5a and Wnt5b genes as well as on comparative genomics for Wnt5a and Wnt5b orthologs.

Amino Acid Sequence↗