Research article summary (published 30 Mar 2007):

AP1- and NF-kappaB-binding sites conserved among mammalian WNT10B orthologs elucidate the TNFalpha-WNT10B signaling loop implicated in carcinogenesis and adipogenesis.

Full Abstract

WNT signals are context-dependently transduced to canonical and non-canonical signaling cascades. We cloned and characterized wild-type human WNT10B, while another group cloned aberrant human WNT10B with Gly60Asp amino-acid substitution. Proto-oncogene WNT10B is expressed in gastric cancer, pancreatic cancer, breast cancer, esophageal cancer, and cervical cancer. Because WNT10B blocks adipocyte differentiation, coding SNP of WNT10B gene is associated with familial obesity. In 2001, we reported WNT10B upregulation by TNFalpha. Here, comparative integromics analyses on WNT10B orthologs were performed to elucidate the transcriptional mechanism of WNT10B. Chimpanzee WNT10B and cow Wnt10b genes were identified within NW_001223159.1 and AC150975.2 genome sequences, respectively, by using bioinformatics (Techint) and human intelligence (Humint). Chimpanzee WNT10B and cow Wnt10b showed 98.7% and 95.1% total-amino-acid identity with human WNT10B, respectively. N-terminal signal peptide, 24 Cys residues, two Asn-linked glycosylation sites, and Gly60 of human WNT10B were conserved among mammalian WNT10B orthologs. Transcription start site of human WNT10B gene was 106-bp upstream of NM_003394.2 RefSeq 5'-end. Number of GC di-nucleotide repeats just down-stream of WNT10B transcription start site varied among primates and human population. Comparative genomics analyses revealed that double AP1-binding sites in the 5'-flanking promoter region and NF-kappaB-binding site in intron 3 were conserved among human, chimpanzee, cow, mouse, and rat WNT10B orthologs. Because TNFalpha signaling through TNFR1 and TRADD/RIP/TRAF2 complex activates JUN kinase (JNK) and IkappaB kinase (IKK) signaling cascades, conserved AP1- and NF-kappaB-binding sites explain the mechanism of TNFalpha-induced WNT10B upregulation. TNFalpha-WNT10B signaling loop is the negative feedback mechanism of adipogenesis to prevent obesity and metabolic syndrome. On the other hand, TNFalpha-WNT10B signaling loop is implicated in carcinogenesis. Inhibitors of TNFalpha-WNT10B signaling loop could be utilized for the prevention or treatment of cancer associated with chronic inflammation, such as gastric, liver, breast and pancreatic cancer.

Author information

Author/s: Katoh, Masuko (M); Katoh, Masaru (M);

Affiliation: M&M Medical BioInformatics, Hongo 113-0033, Japan.

Journal and publication information

Publication Type: Comparative Study; Journal Article

Journal: International journal of molecular medicine (Int J Mol Med), published in Greece. (Language: eng)

Reference: 2007-Apr; vol 19 (issue 4) : pp 699-703

Dates: Created 2007/03/05; Completed 2007/05/02;

PMID: 17334647, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adipogenesis - genetics Amino Acid Sequence Animals Binding Sites Cattle Cell Transformation, Neoplastic - genetics Conserved Sequence Genomics Humans Mice

Molecular Sequence Data NF-kappa B - metabolism Pan troglodytes Proto-Oncogene Proteins - chemistry; genetics; metabolism Rats Signal Transduction Transcription Factor AP-1 - metabolism Transcription Initiation Site Tumor Necrosis Factor-alpha - metabolism Wnt Proteins - chemistry; genetics; metabolism

Associated Chemicals: NF-kappa B (0) ; Proto-Oncogene Proteins (0) ; Transcription Factor AP-1 (0) ; Tumor Necrosis Factor-alpha (0) ; WNT10B protein, human (0) ; Wnt Proteins (0)

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