Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity of<i>GKN3</i>

Geahlen, Jessica H.; Lapid, Carlo M.; Thorell, Kaisa; Nikolskiy, Igor; Huh, Won Jae; Oates, Edward L.; Lennerz, Jochen K.; Tian, Xiaolin; Weis, Victoria G.; Khurana, Sakshi; Lundin, Samuel; Templeton, Alan R.; Mills, Jason C.

doi:10.1152/physiolgenomics.00169.2012

Cited by 15 publications

(14 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The two RAB26 probesets showed strong correlation among the tissues examined (Pearson's correlation coefficient of 0.9145) and mirrored the known tissue distribution of the secretory cell transcription factor MIST1 (Lemercier et al, 1997;Mills and Taghert, 2012;Pin et al, 2000). Moreover, within specific organs, RAB26 expression was confined to MIST1-expressing cell lineages like the serous exocrine, digestive-enzyme-secreting zymogenic (chief) cells of the stomach, but not their precursors, the mucus-secreting 'neck cells' (Capoccia et al, 2013;Geahlen et al, 2013;Fig. 1B).…”

Section: Introductionmentioning

confidence: 74%

RAB26 coordinates lysosome traffic and mitochondrial localization

Jin

Mills

2014

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

As they mature, professional secretory cells like pancreatic acinar and gastric chief cells induce the transcription factor MIST1 (also known as BHLHA15) to substantially scale up production of large secretory granules in a process that involves expansion of apical cytoplasm and redistribution of lysosomes and mitochondria. How a scaling factor like MIST1 rearranges cellular architecture simply by regulating expression levels of its transcriptional targets is unknown. RAB26 is a MIST1 target whose role in MIST1-mediated secretory cell maturation is also unknown. Here, we confirm that RAB26 expression, unlike most Rabs which are ubiquitously expressed, is tissue specific and largely confined to MIST1-expressing secretory tissues. Surprisingly, functional studies showed that RAB26 predominantly associated with LAMP1/cathepsin D lysosomes and not directly with secretory granules. Moreover, increasing RAB26 expression -by inducing differentiation of zymogensecreting cells or by direct transfection -caused lysosomes to coalesce in a central, perinuclear region. Lysosome clustering in turn caused redistribution of mitochondria into distinct subcellular neighborhoods. The data elucidate a novel function for RAB26 and suggest a mechanism for how cells could increase transcription of key effectors to reorganize subcellular compartments during differentiation.

show abstract

Section: Introductionmentioning

confidence: 74%

RAB26 coordinates lysosome traffic and mitochondrial localization

Jin

Mills

2014

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…2). Loss or injury of parietal cells causes chief cells to downscale their large secretory granules containing digestive enzymes like Pepsinogen C and Carboxypeptidase B (74) and re-express markers of mucous neck cells (which are the precursors of chief cells in adult stomachs(75–77)), like TFF2 (Spasmolytic polypeptide), MUC6, the epitope for the lectin GS-II, and, in mice, Gastrokine 3 (69, 73, 78–80). Thus, tissue damage of the type that injures parietal cells causes a complete reorganization of the gastric unit, characterized by, in addition to parietal cell atrophy: expansion of a metaplastic lineage co-expressing mucous neck and chief cell markers and the loss of normal chief cells, as they change their differentiation state to this metaplastic lineage (70, 74, 81, 82).…”

Section: The Process Of Reprogramming and Its Role In Repair Metaplamentioning

confidence: 99%

Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract

2015

Self Cite

View full text Add to dashboard Cite

It has long been known that differentiated cells can switch fates, especially in vitro, but only recently has there been a critical mass of publications describing the mechanisms adult, post-mitotic cells use in vivo to reverse their differentiation state. We propose that this sort of cellular reprogramming is a fundamental cellular process akin to apoptosis or mitosis. Because reprogramming can invoke regenerative cells from mature cells, it is critical to the longterm maintenance of tissues like the pancreas, which encounter large insults during adulthood but lack constitutively active adult stem cells to repair the damage. However, even in tissues with adult stem cells, like stomach and intestine, reprogramming may allow mature cells to serve as reserve (“quiescent”) stem cells when normal stem cells are compromised. We propose that the potential downside to reprogramming is that it increases risk for cancers that occur late in adulthood. Mature, long-lived cells may have years of exposure to mutagens. Mutations that affect the physiological function of differentiated, post-mitotic cells may lead to apoptosis, but mutations in genes that govern proliferation might not be selected against. Hence, reprogramming with reentry into the cell cycle might unmask those mutations, causing an irreversible progenitor-like, proliferative state. We review recent evidence showing that reprogramming fuels irreversible metaplastic and precancerous proliferations in stomach and pancreas. Finally, we illustrate how we think reprogrammed differentiated cells are likely candidates as cells of origin for cancers of the intestine.

show abstract

“…While all BRICHOS proteins are secreted or processed to generate secreted mature peptides, GKNs are unique in being almost exclusively expressed within, and secreted by, mucus-producing epithelial cell lineages of the stomach (6)(7)(8)(9). The 3 GKNs are encoded by a tightly linked gene cluster on human chromosome 2p13.3 and show broad evolutionary conservation in mammals and higher vertebrates (6,10). GKN1 and GKN2 were identified in differential expression screens as novel genes downregulated in GC (7,8,11).…”

Section: Introductionmentioning

confidence: 99%

Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression

Menheniott¹,

O’Connor²,

Chionh³

et al. 2016

Journal of Clinical Investigation

View full text Add to dashboard Cite

Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to a family of secreted proteins expressed within normal gastric mucosal cells. GKN2 expression is frequently lost during GC progression, suggesting an inhibitory role; however, a causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice to investigate the functional impact of GKN2 loss in GC pathogenesis. In mouse models of GC, decreased GKN2 expression correlated with gastric pathology that paralleled human GC progression. At baseline, Gkn2 knockout mice exhibited defective gastric epithelial differentiation but not malignant progression. Conversely, Gkn2 knockout in the IL-11/STAT3-dependent gp130F/F GC model caused tumorigenesis of the proximal stomach. Additionally, gastric immunopathology was accelerated in Helicobacter pylori-infected Gkn2 knockout mice and was associated with augmented T helper cell type 1 (Th1) but not Th17 immunity. Heightened Th1 responses in Gkn2 knockout mice were linked to deregulated mucosal innate immunity and impaired myeloid-derived suppressor cell activation. Finally, transgenic overexpression of human gastrokines (GKNs) attenuated gastric tumor growth in gp130F/F mice. Together, these results reveal an antiinflammatory role for GKN2, provide in vivo evidence that links GKN2 loss to GC pathogenesis, and suggest GKN restoration as a strategy to restrain GC progression.

show abstract

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

Cited by 15 publications

References 54 publications

RAB26 coordinates lysosome traffic and mitochondrial localization

RAB26 coordinates lysosome traffic and mitochondrial localization

Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract

Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression

Contact Info

Product

Resources

About