A novel gastrokine, Gkn3, marks gastric atrophy and shows evidence of adaptive gene loss in humans

Gastroenterology. 2010 May;138(5):1823-35. doi: 10.1053/j.gastro.2010.01.050. Epub 2010 Feb 4.

Abstract

Background & aims: Gastrokines are stomach mucus cell-secreted proteins; 2 gastrokines are known, GKN1 and GKN2. Gastrokine expression is lost in gastric cancer, indicating a possible function in tumor suppression. We have identified a third gastrokine gene in mammals.

Methods: Gkn3 was characterized by studies of molecular structure, evolutionary conservation, and tissue expression as well as transcriptional/translational outcome in mouse genetic models of gastric pathology. The functional consequences of Gkn3 overexpression were evaluated in transfected cell lines.

Results: Gkn3 encodes a secreted (approximately 19 kilodalton) protein that is co-expressed with trefoil factor (Tff)2 in the distal stomach and discriminates a Griffinia simplicifolia lectin (GS)-II-positive mucus neck cell (MNC) subpopulation in the proximal stomach. In humans, widespread homozygosity for a premature stop codon polymorphism, W59X, has likely rendered GKN3 non-functional. Population genetic analysis revealed an ancestral GKN3 read-through allele that predominates in Africans and indicates the rapid expansion of W59X among non-Africans during recent evolution. Mouse Gkn3 expression is strongly up-regulated in (Tff2-deficient) gastric atrophy, a pre-cancerous state that is typically associated with Helicobacter pylori and marks a non-proliferative, GS-II positive lineage with features of spasmolytic polypeptide-expressing metaplasia (SPEM). Gkn3 overexpression inhibits proliferation in gastric epithelial cell lines, independently of incubation with recombinant human TFF2 or apoptosis.

Conclusions: Gkn3 encodes a novel, functionally distinct gastrokine that is overexpressed and might restrain epithelial cell proliferation in gastric atrophy. Spread of the human GKN3 stop allele W59X might have been selected for among non-Africans because of its effects on pre-neoplastic outcomes in the stomach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / genetics
  • African Continental Ancestry Group / genetics
  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Asian Continental Ancestry Group / genetics
  • Atrophy
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Line
  • Cell Proliferation
  • Codon, Nonsense
  • Conserved Sequence
  • Disease Models, Animal
  • European Continental Ancestry Group / genetics
  • Evolution, Molecular
  • Gastric Mucosa / metabolism*
  • Gastric Mucosa / pathology
  • Gene Frequency
  • Genotype
  • Homozygote
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Metaplasia
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Mucins / deficiency
  • Mucins / genetics
  • Mucins / metabolism
  • Muscle Proteins / deficiency
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Pan troglodytes
  • Peptides / deficiency
  • Peptides / genetics
  • Peptides / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Precancerous Conditions / genetics*
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology
  • Recombinant Proteins / metabolism
  • Stomach / pathology
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • Time Factors
  • Transfection
  • Trefoil Factor-2

Substances

  • Carrier Proteins
  • Codon, Nonsense
  • GKN3P protein, human
  • Membrane Proteins
  • Mucins
  • Muscle Proteins
  • Peptides
  • Recombinant Proteins
  • TFF2 protein, human
  • TFF2 protein, mouse
  • Trefoil Factor-2
  • gastrokine 3 protein, mouse

Associated data

  • GENBANK/GU220566
  • GENBANK/GU228900