PMID- 19023031
OWN - NLM
STAT- MEDLINE
DCOM- 20090226
LR  - 20220410
IS  - 0193-1857 (Print)
IS  - 0193-1857 (Linking)
VI  - 296
IP  - 1
DP  - 2009 Jan
TI  - Requirement of Notch activation during regeneration of the intestinal epithelia.
PG  - G23-35
LID - 10.1152/ajpgi.90225.2008 [doi]
AB  - Notch signaling regulates cell differentiation and proliferation, contributing to 
      the maintenance of diverse tissues including the intestinal epithelia. However, 
      its role in tissue regeneration is less understood. Here, we show that Notch 
      signaling is activated in a greater number of intestinal epithelial cells in the 
      inflamed mucosa of colitis. Inhibition of Notch activation in vivo using a 
      gamma-secretase inhibitor resulted in a severe exacerbation of the colitis 
      attributable to the loss of the regenerative response within the epithelial 
      layer. Activation of Notch supported epithelial regeneration by suppressing 
      goblet cell differentiation, but it also promoted cell proliferation, as shown in 
      in vivo and in vitro studies. By utilizing tetracycline-dependent gene expression 
      and microarray analysis, we identified a novel group of genes that are regulated 
      downstream of Notch1 within intestinal epithelial cells, including PLA2G2A, an 
      antimicrobial peptide secreted by Paneth cells. Finally, we show that these 
      functions of activated Notch1 are present in the mucosa of ulcerative colitis, 
      mediating cell proliferation, goblet cell depletion, and ectopic expression of 
      PLA2G2A, thereby contributing to the regeneration of the damaged epithelia. This 
      study showed the critical involvement of Notch signaling during intestinal tissue 
      regeneration, regulating differentiation, proliferation, and antimicrobial 
      response of the epithelial cells. Thus Notch signaling is a key intracellular 
      molecular pathway for the proper reconstruction of the intestinal epithelia.
FAU - Okamoto, Ryuichi
AU  - Okamoto R
AD  - Dept. of Advanced Therapeutics in Gastrointestinal Diseases, Graduate School, 
      Tokyo Medical and Dental Univ., 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
FAU - Tsuchiya, Kiichiro
AU  - Tsuchiya K
FAU - Nemoto, Yasuhiro
AU  - Nemoto Y
FAU - Akiyama, Junko
AU  - Akiyama J
FAU - Nakamura, Tetsuya
AU  - Nakamura T
FAU - Kanai, Takanori
AU  - Kanai T
FAU - Watanabe, Mamoru
AU  - Watanabe M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081120
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 0 (Azepines)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hes1 protein, mouse)
RN  - 0 (Homeodomain Proteins)
RN  - 0 
      (N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide)
RN  - 0 (NOTCH1 protein, human)
RN  - 0 (Notch1 protein, mouse)
RN  - 0 (Receptor, Notch1)
RN  - 0 (Receptors, Notch)
RN  - 0 (Transcription Factor HES-1)
RN  - 149348-15-2 (HES1 protein, human)
RN  - 9042-14-2 (Dextran Sulfate)
RN  - EC 3.1.1.4 (Group II Phospholipases A2)
RN  - EC 3.1.1.4 (PLA2G2A protein, human)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - OF5P57N2ZX (Alanine)
SB  - IM
MH  - Alanine/analogs & derivatives/pharmacology
MH  - Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
MH  - Animals
MH  - Azepines/pharmacology
MH  - Basic Helix-Loop-Helix Transcription Factors/metabolism
MH  - Cell Differentiation
MH  - Cell Proliferation
MH  - Colitis/chemically induced/*metabolism/pathology
MH  - Colon/drug effects/*metabolism/pathology
MH  - Dextran Sulfate
MH  - Disease Models, Animal
MH  - Enzyme Inhibitors/pharmacology
MH  - Goblet Cells/metabolism/pathology
MH  - Group II Phospholipases A2/metabolism
MH  - HT29 Cells
MH  - Homeodomain Proteins/metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Paneth Cells/metabolism/pathology
MH  - Receptor, Notch1/metabolism
MH  - Receptors, Notch/genetics/*metabolism
MH  - *Regeneration/drug effects
MH  - *Signal Transduction/drug effects
MH  - Transcription Factor HES-1
EDAT- 2008/11/22 09:00
MHDA- 2009/02/27 09:00
CRDT- 2008/11/22 09:00
PHST- 2008/11/22 09:00 [pubmed]
PHST- 2009/02/27 09:00 [medline]
PHST- 2008/11/22 09:00 [entrez]
AID - 90225.2008 [pii]
AID - 10.1152/ajpgi.90225.2008 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2009 Jan;296(1):G23-35. doi: 
      10.1152/ajpgi.90225.2008. Epub 2008 Nov 20.