PMID- 22696685
OWN - NLM
STAT- MEDLINE
DCOM- 20130403
LR  - 20211203
IS  - 1939-4586 (Electronic)
IS  - 1059-1524 (Print)
IS  - 1059-1524 (Linking)
VI  - 23
IP  - 15
DP  - 2012 Aug
TI  - Nuclear factor of activated T-cell c3 inhibition of mammalian target of rapamycin 
      signaling through induction of regulated in development and DNA damage response 1 
      in human intestinal cells.
PG  - 2963-72
LID - 10.1091/mbc.E12-01-0037 [doi]
AB  - The nuclear factor of activated T-cell (NFAT) proteins are a family of 
      transcription factors (NFATc1-c4) involved in the regulation of cell 
      differentiation. We identified REDD1, a negative regulator of mammalian target of 
      rapamycin (mTOR) through the tuberous sclerosis complex (TSC1/2 complex), as a 
      new molecular target of NFATc3. We show that treatment with a combination of 
      phorbol 12-myristate 13-acetate (PMA) plus ionophore A23187 (Io), which induces 
      NFAT activation, increased REDD1 mRNA and protein expression and inhibited mTOR 
      signaling; pretreatment with the calcineurin inhibitor cyclosporin A (CsA), an 
      antagonist of NFAT signaling, decreased REDD1 induction and mTOR inhibition. 
      Knockdown of NFATc3, not NFATc1, NFATc2, or NFATc4, attenuated PMA/Io-induced 
      REDD1 expression. Treatment with PMA/Io increased REDD1 promoter activity and 
      increased NFATc3 binding to the REDD1 promoter. Overexpression of NFATc3 
      increased REDD1 mRNA and protein expression and increased PMA/Io-mediated REDD1 
      promoter activity. Treatment with PMA/Io increased expression of the goblet cell 
      differentiation marker MUC2; these changes were attenuated by pretreatment with 
      CsA or knockdown of REDD1 or NFATc3. Overexpression of NFATc3 increased, while 
      knockdown of TSC2 decreased, MUC2 expression. We provide evidence showing NFATc3 
      inhibits mTOR via induction of REDD1. Our results suggest a role for the 
      NFATc3/REDD1/TSC2 axis in the regulation of intestinal cell differentiation.
FAU - Zhou, Yuning
AU  - Zhou Y
AD  - Markey Cancer Center, University of Kentucky, Lexington, KY 40536-0293, USA.
FAU - Wang, Qingding
AU  - Wang Q
FAU - Guo, Zheng
AU  - Guo Z
FAU - Weiss, Heidi L
AU  - Weiss HL
FAU - Evers, B Mark
AU  - Evers BM
LA  - eng
GR  - P20 CA150343/CA/NCI NIH HHS/United States
GR  - R01 DK048498/DK/NIDDK NIH HHS/United States
GR  - R01-DK48498/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120613
PL  - United States
TA  - Mol Biol Cell
JT  - Molecular biology of the cell
JID - 9201390
RN  - 0 (Calcineurin Inhibitors)
RN  - 0 (DDIT4 protein, human)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (TSC1 protein, human)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 37H9VM9WZL (Calcimycin)
RN  - 57716-89-9 (4-O-methyl-12-O-tetradecanoylphorbol 13-acetate)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - Calcimycin/pharmacology
MH  - Calcineurin Inhibitors
MH  - *Cell Differentiation/drug effects/genetics
MH  - Cyclosporine/pharmacology
MH  - Gene Expression Regulation/drug effects
MH  - HCT116 Cells
MH  - HT29 Cells
MH  - Humans
MH  - *Intestinal Mucosa/metabolism
MH  - *Intestines/cytology/growth & development
MH  - NFATC Transcription Factors/*metabolism
MH  - Signal Transduction/drug effects
MH  - *TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - Tetradecanoylphorbol Acetate/analogs & derivatives/pharmacology
MH  - Transcription Factors/genetics/*metabolism
MH  - Tuberous Sclerosis Complex 1 Protein
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Suppressor Proteins/metabolism
PMC - PMC3408422
EDAT- 2012/06/15 06:00
MHDA- 2013/04/04 06:00
PMCR- 2012/10/16
CRDT- 2012/06/15 06:00
PHST- 2012/06/15 06:00 [entrez]
PHST- 2012/06/15 06:00 [pubmed]
PHST- 2013/04/04 06:00 [medline]
PHST- 2012/10/16 00:00 [pmc-release]
AID - mbc.E12-01-0037 [pii]
AID - E12-01-0037 [pii]
AID - 10.1091/mbc.E12-01-0037 [doi]
PST - ppublish
SO  - Mol Biol Cell. 2012 Aug;23(15):2963-72. doi: 10.1091/mbc.E12-01-0037. Epub 2012 
      Jun 13.