A Novel Gastrokine, Gkn3, Marks Gastric Atrophy and Shows Evidence of Adaptive Gene Loss in Humans

Menheniott, Trevelyan R.; Peterson, A. J.; O’Connor, Louise; Lee, Kai Syin; Kalantzis, Anastasia; Kondova, Ivanela; Bontrop, Ronald E.; Bell, Katrina M.; Giraud, Andrew S.

doi:10.1053/j.gastro.2010.01.050

Cited by 50 publications

(88 citation statements)

References 31 publications

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“…1, B and C). From this analysis, RIKEN cDNA 1190003M12Rik [later independently identified as GKN3 by Menheniott et al (25)] was the only gene to have both a prominent neck cell-enriched and stomachspecific expression pattern (Fig. 1, B and C).…”

Section: Resultsmentioning

confidence: 99%

“…However, there are no reported ESTs representing GKN3 in human libraries, and it is not clear whether GKN3 is expressed in humans or is a pseudogene. While we were analyzing sequence and expression of Gkn3, Menheniott et al (25) reported their analysis of the same gene (Fig. 6A), finding it to be neck cell specific in mice.…”

Section: Resultsmentioning

confidence: 99%

“…But in humans, they reported a SNP, rs10187256, in the predicted (by conservation) third exon that would mutate, by means of the G-A substitution, a highly conserved tryptophan to a premature STOP codon (Fig. 6, B and C) (25). We next decided to analyze GKN3 sequence evolution and conservation among populations of humans in an attempt to learn more about this SNP and possible functionality of the gene in various human populations.…”

Section: Resultsmentioning

confidence: 99%

“…GKN3 has a stomach-specific expression pattern and is expressed at relatively higher levels in cells during the gastric atrophy that occurs, for example, during infection with Helicobacter pylori. Interestingly, a nonsense mutation in GKN3 exon 3 was found to have a high frequency in non-African populations, hinting at population-specific patterns of positive selection favoring nonfunctionality (25). However, this gene's evolution, patterns of expression, and function in humans, if any, have not been examined.…”

mentioning

confidence: 99%

“…The most recently discovered GKN is gastrokine 3 (GKN3) (25). GKN3 has a stomach-specific expression pattern and is expressed at relatively higher levels in cells during the gastric atrophy that occurs, for example, during infection with Helicobacter pylori.…”

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confidence: 99%

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Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity ofGKN3

Geahlen

Lapid

Thorell

et al. 2013

Physiological Genomics

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Templeton AR, Mills JC. Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity of GKN3. Physiol Genomics 45: 667-683, 2013. First published May 28, 2013 doi:10.1152/physiolgenomics.00169.2012.-In a screen for genes expressed specifically in gastric mucous neck cells, we identified GKN3, the recently discovered third member of the gastrokine family. We present confirmatory mouse data and novel porcine data showing that mouse GKN3 expression is confined to mucous cells of the corpus neck and antrum base and is prominently expressed in metaplastic lesions. GKN3 was proposed originally to be expressed in some human populations and a pseudogene in others. To investigate that hypothesis, we studied human GKN3 evolution in the context of its paralogous genomic neighbors, GKN1 and GKN2. Haplotype analysis revealed that GKN3 mimics GKN2 in patterns of exonic SNP allocation, whereas GKN1 appeared to be more stringently selected. GKN3 showed signatures of both directional selection and population based selective sweeps in humans. One such selective sweep includes SNP rs10187256, originally identified as an ancestral tryptophan to premature STOP codon mutation. The derived (nonancestral) allele went to fixation in Asia. We show that another SNP, rs75578132, identified 5 bp downstream of rs10187256, exhibits a second selective sweep in almost all Europeans, some Latinos, and some Africans, possibly resulting from a reintroduction of European genes during African colonization. Finally, we identify a mutation that would destroy the splice donor site in the putative exon3-intron3 boundary, which occurs in all human genomes examined to date. Our results highlight a stomach-specific human genetic locus, which has undergone various selective sweeps across European, Asian, and African populations and thus reflects geographic and ethnic patterns in genome evolution.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity ofGKN3

Geahlen

Lapid

Thorell

et al. 2013

Physiological Genomics

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Overexpression of gastrokine 1 in gastric cancer cells induces Fas‐mediated apoptosis

Rippa

Monica

Allocca

et al. 2011

Journal Cellular Physiology

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Gastrokine 1 (GKN1) is involved in the replenishment of the surface lumen epithelial cell layer, in maintaining the mucosal integrity, and could play a role in cell proliferation and differentiation. In fact, after injury of the gastric mucosa, restoration may occur very rapidly in the presence of GKN1. In contrast, if the protein is downregulated, the repair process may be hampered; however, application of GKN1 to gastrointestinal cells promoted epithelial restoration. Because GKN1 possesses some mitogenic effects on intestinal epithelial cells (IEC-6) whereas this protein was also capable of inhibiting proliferation in gastric cancer cells (MKN28), we decided to study its involvement in apoptosis to understand the role of GKN1 in the modulation of inflammatory damage or tumorigenesis in gastric mucosa. We found by cytofluorimetry, Western blot and RT-PCR that the overexpression of GKN1 in gastric cancer cell lines (AGS and MKN28) stimulated the expression of Fas receptor. Moreover, compared to control cells, a significant increase of apoptosis, evaluated by TUNEL, was observed when GKN1 transfected cells were treated with a monoclonal antibody (IgM) anti-Fas. The activation of Fas expression was also observed by the overexpression of GKN1 in other cancer cell lines. Moreover, in GKN1-overexpressing gastric cancer cells exposed to FasL, the activation of caspase-3 was also observed by Western blot and fluorescence assays. Our data represent the first report for GKN1 as modulator of apoptotic signals and suggest that GKN1 might play an important role for tissue repair during the early stages of neoplastic transformation.

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Proteomics characterization of gastrokine 1‐induced growth inhibition of gastric cancer cells

Yan

Tan

et al. 2011

Proteomics

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We previously used proteomics technology to globally identify gastric cancer-associated proteins and found that gastrokine 1 (GKN1) was dramatically underexpressed in gastric cancer tissues. Here, we further showed that GKN1 could inhibit cell growth and induce cell cycle arrest in gastric cancer cells. The activity of protein kinase PKCδ/θ was inhibited by GKN1, whereas the activity of ERK1/2 and JNK1/2 was increased by GKN1, suggesting that GKN1 induced growth inhibition of gastric cancer cells by synergistically regulating the activity of these protein kinases. Seventy-four proteins were found to be regulated by GKN1 by proteomics analysis, including α-enolase (ENO1) and Cathepsin D. Interestingly, ENO1 is an important hub in the protein-protein interaction network of the 74 differential proteins. Silencing of ENO1 resulted in growth inhibition and cell cycle arrest of gastric cancer cells, similar to the effect of GKN1 overexpression in cells, whereas ENO1 overexpression blocked GKN1-induced growth inhibition and cell cycle arrest. These observations suggested that ENO1 downregulation played an important role in GKN1-induced growth inhibition of gastric cancer cells.

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A Novel Gastrokine, Gkn3, Marks Gastric Atrophy and Shows Evidence of Adaptive Gene Loss in Humans

Cited by 50 publications

References 31 publications

Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity ofGKN3

Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity ofGKN3

Overexpression of gastrokine 1 in gastric cancer cells induces Fas‐mediated apoptosis

Proteomics characterization of gastrokine 1‐induced growth inhibition of gastric cancer cells

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