PMID- 28859856
OWN - NLM
STAT- MEDLINE
DCOM- 20171205
LR  - 20240210
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Print)
IS  - 0016-5085 (Linking)
VI  - 153
IP  - 6
DP  - 2017 Dec
TI  - Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric 
      Glial Cells.
PG  - 1555-1567.e15
LID - S0016-5085(17)36071-7 [pii]
LID - 10.1053/j.gastro.2017.08.038 [doi]
AB  - BACKGROUND & AIMS: The multiple endocrine neoplasia, type 1 (MEN1) locus encodes 
      the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause 
      neuroendocrine tumors such as gastrinomas, characterized by their predominant 
      duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell 
      hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within 
      submucosal Brunner's glands. We investigated how menin regulates expression of 
      the gastrin gene and induces generation of submucosal gastrin-expressing cell 
      hyperplasia. METHODS: Primary enteric glial cultures were generated from the 
      VillinCre:Men1(FL/FL):Sst(-/-) mice or C57BL/6 mice (controls), with or without 
      inhibition of gastric acid by omeprazole. Primary enteric glial cells from 
      C57BL/6 mice were incubated with gastrin and separated into nuclear and 
      cytoplasmic fractions. Cells were incubated with forskolin and H89 to activate or 
      inhibit protein kinase A (a family of enzymes whose activity depends on cellular 
      levels of cyclic AMP). Gastrin was measured in blood, tissue, and cell cultures 
      using an ELISA. Immunoprecipitation with menin or ubiquitin was used to 
      demonstrate post-translational modification of menin. Primary glial cells were 
      incubated with leptomycin b and MG132 to block nuclear export and proteasome 
      activity, respectively. We obtained human duodenal, lymph node, and pancreatic 
      gastrinoma samples, collected from patients who underwent surgery from 1996 
      through 2007 in the United States or the United Kingdom. RESULTS: Enteric glial 
      cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed 
      gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear 
      export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of 
      PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the 
      proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), 
      colocalized with gastrin in human duodenal gastrinomas. CONCLUSIONS: 
      MEN1-associated gastrinomas, which develop in the submucosa, might arise 
      from enteric glial cells through hormone-dependent PKA signaling. This pathway 
      disrupts nuclear menin function, leading to hypergastrinemia and associated 
      sequelae.
CI  - Copyright (c) 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Sundaresan, Sinju
AU  - Sundaresan S
AD  - Department of Internal Medicine, Division of Gastroenterology, University of 
      Michigan, Ann Arbor, Michigan.
FAU - Meininger, Cameron A
AU  - Meininger CA
AD  - Department of Internal Medicine, Division of Gastroenterology, University of 
      Michigan, Ann Arbor, Michigan.
FAU - Kang, Anthony J
AU  - Kang AJ
AD  - Department of Internal Medicine, Division of Gastroenterology, University of 
      Michigan, Ann Arbor, Michigan.
FAU - Photenhauer, Amanda L
AU  - Photenhauer AL
AD  - Department of Internal Medicine, Division of Gastroenterology, University of 
      Michigan, Ann Arbor, Michigan.
FAU - Hayes, Michael M
AU  - Hayes MM
AD  - Department of Internal Medicine, Division of Gastroenterology, University of 
      Michigan, Ann Arbor, Michigan.
FAU - Sahoo, Nirakar
AU  - Sahoo N
AD  - Department of Molecular, Cellular, and Developmental Biology, University of 
      Michigan, Ann Arbor, Michigan.
FAU - Grembecka, Jolanta
AU  - Grembecka J
AD  - Department of Pathology, University of Michigan, Ann Arbor, Michigan.
FAU - Cierpicki, Tomasz
AU  - Cierpicki T
AD  - Department of Pathology, University of Michigan, Ann Arbor, Michigan.
FAU - Ding, Lin
AU  - Ding L
AD  - Department of Internal Medicine, Division of Gastroenterology, University of 
      Michigan, Ann Arbor, Michigan.
FAU - Giordano, Thomas J
AU  - Giordano TJ
AD  - Department of Pathology, University of Michigan, Ann Arbor, Michigan.
FAU - Else, Tobias
AU  - Else T
AD  - Division of Metabolism Endocrinology and Diabetes, University of Michigan, Ann 
      Arbor, Michigan.
FAU - Madrigal, David J
AU  - Madrigal DJ
AD  - Endocrine Oncology Program, University of Michigan, Ann Arbor, Michigan.
FAU - Low, Malcolm J
AU  - Low MJ
AD  - Department of Molecular and Integrative Physiology, University of Michigan, Ann 
      Arbor, Michigan.
FAU - Campbell, Fiona
AU  - Campbell F
AD  - Department of Pathology, Royal Liverpool University Hospital, Liverpool, United 
      Kingdom.
FAU - Baker, Ann-Marie
AU  - Baker AM
AD  - Center for Tumour Biology, Barts Cancer Institute, Queen Mary University of 
      London, London, United Kingdom.
FAU - Xu, Haoxing
AU  - Xu H
AD  - Department of Molecular, Cellular, and Developmental Biology, University of 
      Michigan, Ann Arbor, Michigan.
FAU - Wright, Nicholas A
AU  - Wright NA
AD  - Center for Tumour Biology, Barts Cancer Institute, Queen Mary University of 
      London, London, United Kingdom.
FAU - Merchant, Juanita L
AU  - Merchant JL
AD  - Department of Internal Medicine, Division of Gastroenterology, University of 
      Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative 
      Physiology, University of Michigan, Ann Arbor, Michigan. Electronic address: 
      merchanj@med.umich.edu.
LA  - eng
GR  - R01 DK115474/DK/NIDDK NIH HHS/United States
GR  - P30 CA046592/CA/NCI NIH HHS/United States
GR  - R01 CA160467/CA/NCI NIH HHS/United States
GR  - R01 NS062792/NS/NINDS NIH HHS/United States
GR  - P30 DK034933/DK/NIDDK NIH HHS/United States
GR  - R37 DK045729/DK/NIDDK NIH HHS/United States
GR  - R01 CA200660/CA/NCI NIH HHS/United States
GR  - 14895/CRUK_/Cancer Research UK/United Kingdom
GR  - R01 DK066604/DK/NIDDK NIH HHS/United States
GR  - R01 DK045729/DK/NIDDK NIH HHS/United States
GR  - R01 AR060837/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20170830
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Gastrins)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (MEN1 protein, human)
RN  - 0 (Men1 protein, mouse)
RN  - 0 (Proteasome Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Proton Pump Inhibitors)
RN  - 0 (Receptor, Cholecystokinin B)
RN  - 0 (Receptors, Somatostatin)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
CIN - Gastroenterology. 2017 Dec;153(6):1473-1475. PMID: 29100851
MH  - Active Transport, Cell Nucleus
MH  - Animals
MH  - Cells, Cultured
MH  - Cyclic AMP-Dependent Protein Kinases/metabolism
MH  - Duodenal Neoplasms/enzymology/genetics/pathology
MH  - Duodenum/drug effects/*metabolism/pathology
MH  - Gastrinoma/enzymology/genetics/pathology
MH  - Gastrins/genetics/*metabolism
MH  - Gene Expression Regulation
MH  - Glial Fibrillary Acidic Protein/metabolism
MH  - Humans
MH  - Hyperplasia
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neuroglia/drug effects/*enzymology
MH  - Proteasome Endopeptidase Complex/*metabolism
MH  - Proteasome Inhibitors/pharmacology
MH  - Proteolysis
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Proton Pump Inhibitors/pharmacology
MH  - Receptor, Cholecystokinin B/metabolism
MH  - Receptors, Somatostatin/genetics/metabolism
MH  - Time Factors
MH  - Ubiquitination
PMC - PMC5705278
MID - NIHMS903070
OTO - NOTNLM
OT  - CCKBR
OT  - GFAP
OT  - MEN1
OT  - Omeprazole
OT  - Somatostatin
OT  - Ubiquitin
COIS- Conflict of Interest: The authors declare no conflict of interest. Competing 
      Financial Interests Drs. Grembecka and Cierpicki receive research support from 
      Kura Oncology. They are also receiving compensation as members of the scientific 
      advisory board of Kura Oncology, and they have an equity ownership in the 
      company.
EDAT- 2017/09/02 06:00
MHDA- 2017/12/06 06:00
PMCR- 2018/12/01
CRDT- 2017/09/02 06:00
PHST- 2017/02/23 00:00 [received]
PHST- 2017/07/31 00:00 [revised]
PHST- 2017/08/13 00:00 [accepted]
PHST- 2017/09/02 06:00 [pubmed]
PHST- 2017/12/06 06:00 [medline]
PHST- 2017/09/02 06:00 [entrez]
PHST- 2018/12/01 00:00 [pmc-release]
AID - S0016-5085(17)36071-7 [pii]
AID - 10.1053/j.gastro.2017.08.038 [doi]
PST - ppublish
SO  - Gastroenterology. 2017 Dec;153(6):1555-1567.e15. doi: 
      10.1053/j.gastro.2017.08.038. Epub 2017 Aug 30.