PMID- 22766853
OWN - NLM
STAT- MEDLINE
DCOM- 20121127
LR  - 20211021
IS  - 1522-1547 (Electronic)
IS  - 0193-1857 (Print)
IS  - 0193-1857 (Linking)
VI  - 303
IP  - 6
DP  - 2012 Sep 15
TI  - Conditional deletion of menin results in antral G cell hyperplasia and 
      hypergastrinemia.
PG  - G752-64
LID - 10.1152/ajpgi.00109.2012 [doi]
AB  - Antral gastrin is the hormone known to stimulate acid secretion and proliferation 
      of the gastric corpus epithelium. Patients with mutations in the multiple 
      endocrine neoplasia type 1 (MEN1) locus, which encodes the protein menin, develop 
      pituitary hyperplasia, insulinomas, and gastrinomas in the duodenum. We 
      previously hypothesized that loss of menin leads to derepression of the gastrin 
      gene and hypergastrinemia. Indeed, we show that menin represses JunD induction of 
      gastrin in vitro. Therefore, we examined whether conditional deletion of Men1 
      (Villin-Cre and Lgr5-EGFP-IRES-CreERT2), with subsequent loss of menin from the 
      gastrointestinal epithelium, increases gastrin expression. We found that 
      epithelium-specific deletion of Men1 using Villin-Cre increased plasma gastrin, 
      antral G cell numbers, and gastrin expression in the antrum, but not the 
      duodenum. Moreover, the mice were hypochlorhydric by 12 mo of age, and gastric 
      somatostatin mRNA levels were reduced. However, duodenal mRNA levels of the 
      cyclin-dependent kinase inhibitor p27(Kip1) were decreased, and cell 
      proliferation determined by Ki67 staining was increased. About 11% of the 
      menin-deficient mice developed antral tumors that were negative for gastrin; 
      however, gastrinomas were not observed, even at 12 mo of age. No gastrinomas were 
      observed with conditional deletion of Men1 in the Lgr5 stem cells 5 mo after Cre 
      induction. In summary, epithelium-specific deletion of the Men1 locus resulted in 
      hypergastrinemia due to antral G cell hyperplasia and a hyperproliferative 
      epithelium, but no gastrinomas. This result suggests that additional mutations in 
      gene targets other than the Men1 locus are required to produce gastrin-secreting 
      tumors.
FAU - Veniaminova, Natalia A
AU  - Veniaminova NA
AD  - Division of Gastroenterology, Department of Internal Medicine, University of 
      Michigan, Ann Arbor, 48109-2200, USA.
FAU - Hayes, Michael M
AU  - Hayes MM
FAU - Varney, Jessica M
AU  - Varney JM
FAU - Merchant, Juanita L
AU  - Merchant JL
LA  - eng
GR  - P01 DK062041/DK/NIDDK NIH HHS/United States
GR  - P30 DK-34933/DK/NIDDK NIH HHS/United States
GR  - R37 DK045729/DK/NIDDK NIH HHS/United States
GR  - R01 DK045729/DK/NIDDK NIH HHS/United States
GR  - R37 DK-45729/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120705
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 0 (Men1 protein, mouse)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 51110-01-1 (Somatostatin)
SB  - IM
MH  - Animals
MH  - Gastrin-Secreting Cells/*physiology
MH  - Gastrointestinal Tract/metabolism
MH  - Gene Deletion
MH  - Gene Expression Regulation/physiology
MH  - Genotype
MH  - Hyperplasia/genetics/metabolism/*pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Pyloric Antrum/*cytology
MH  - Somatostatin/metabolism
PMC - PMC3468536
EDAT- 2012/07/07 06:00
MHDA- 2012/12/10 06:00
PMCR- 2013/09/15
CRDT- 2012/07/07 06:00
PHST- 2012/07/07 06:00 [entrez]
PHST- 2012/07/07 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
PHST- 2013/09/15 00:00 [pmc-release]
AID - ajpgi.00109.2012 [pii]
AID - GI-00109-2012 [pii]
AID - 10.1152/ajpgi.00109.2012 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2012 Sep 15;303(6):G752-64. doi: 
      10.1152/ajpgi.00109.2012. Epub 2012 Jul 5.