PMID- 25561726
OWN - NLM
STAT- MEDLINE
DCOM- 20150511
LR  - 20220331
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 290
IP  - 9
DP  - 2015 Feb 27
TI  - Glycogen synthase kinase-3 (GSK3) inhibition induces prosurvival autophagic 
      signals in human pancreatic cancer cells.
PG  - 5592-605
LID - 10.1074/jbc.M114.616714 [doi]
AB  - Glycogen synthase kinase-3 (GSK3) are ubiquitously expressed serine-threonine 
      kinases involved in a plethora of functions ranging from the control of glycogen 
      metabolism to transcriptional regulation. We recently demonstrated that GSK3 
      inhibition triggers JNK-cJUN-dependent apoptosis in human pancreatic cancer 
      cells. However, the comprehensive picture of downstream GSK3-regulated 
      pathways/functions remains elusive. Herein, counterbalancing the death signals, 
      we show that GSK3 inhibition induces prosurvival signals through increased 
      activity of the autophagy/lysosomal network. Our data also reveal a contribution 
      of GSK3 in the regulation of the master transcriptional regulator of autophagy 
      and lysosomal biogenesis, transcription factor EB (TFEB) in pancreatic cancer 
      cells. Similarly to mammalian target of rapamycin (mTOR) inhibition, GSK3 
      inhibitors promote TFEB nuclear localization and leads to TFEB dephosphorylation 
      through endogenous serine/threonine phosphatase action. However, GSK3 and mTOR 
      inhibition impinge differently and independently on TFEB phosphorylation 
      suggesting that TFEB is regulated by a panel of kinases and/or phosphatases. 
      Despite their differential impact on TFEB phosphorylation, both GSK3 and mTOR 
      inhibitors promote 14-3-3 dissociation and TFEB nuclear localization. 
      Quantitative mass spectrometry analyses further reveal an increased association 
      of TFEB with nuclear proteins upon GSK3 and mTOR inhibition suggesting a positive 
      impact on TFEB transcriptional function. Finally, a predominant nuclear 
      localization of TFEB is unveiled in fully fed pancreatic cancer cells, whereas a 
      reduction in TFEB expression significantly impairs their capacity for growth in 
      an anchorage-independent manner. In addition, TFEB-restricted cells are more 
      sensitive to apoptosis upon GSK3 inhibition. Altogether, our data uncover new 
      functions under the control of GSK3 in pancreatic cancer cells in addition to 
      providing key insight into TFEB regulation.
CI  - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Marchand, Benoit
AU  - Marchand B
AD  - From the Department of Medicine, Gastroenterology Division, and.
FAU - Arsenault, Dominique
AU  - Arsenault D
AD  - From the Department of Medicine, Gastroenterology Division, and.
FAU - Raymond-Fleury, Alexandre
AU  - Raymond-Fleury A
AD  - From the Department of Medicine, Gastroenterology Division, and.
FAU - Boisvert, Francois-Michel
AU  - Boisvert FM
AD  - the Department of Anatomy and Cell Biology, Faculte de Medecine et des Sciences 
      de la Sante, Pavillon de Recherche Appliquee sur le Cancer, Universite de 
      Sherbrooke, Sherbrooke, Quebec J1E 4K8, Canada.
FAU - Boucher, Marie-Josee
AU  - Boucher MJ
AD  - From the Department of Medicine, Gastroenterology Division, and 
      marie-josee.boucher@usherbrooke.ca.
LA  - eng
GR  - MOP-106456/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150105
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 
      (1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one)
RN  - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
RN  - 0 (Chir 99021)
RN  - 0 (Naphthyridines)
RN  - 0 (Pyridines)
RN  - 0 (Pyrimidines)
RN  - 0 (TFEB protein, human)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - Active Transport, Cell Nucleus/drug effects
MH  - Animals
MH  - Apoptosis/drug effects/genetics
MH  - Autophagy/*drug effects/genetics
MH  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cell Nucleus/metabolism
MH  - Cell Survival/drug effects/genetics
MH  - Cells, Cultured
MH  - Glycogen Synthase Kinase 3/*antagonists & inhibitors/genetics/metabolism
MH  - Green Fluorescent Proteins/genetics/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Immunoblotting
MH  - Mass Spectrometry
MH  - Mice, Knockout
MH  - Microscopy, Confocal
MH  - Naphthyridines/pharmacology
MH  - Pancreatic Neoplasms/genetics/metabolism/pathology
MH  - Pyridines/*pharmacology
MH  - Pyrimidines/*pharmacology
MH  - RNA Interference
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
PMC - PMC4342473
OTO - NOTNLM
OT  - 14-3-3 Protein
OT  - Apoptosis
OT  - Autophagy
OT  - Glycogen Synthase Kinase 3 (GSK-3)
OT  - Pancreatic Cancer
OT  - Transcription Factor
EDAT- 2015/01/07 06:00
MHDA- 2015/05/12 06:00
PMCR- 2016/02/27
CRDT- 2015/01/07 06:00
PHST- 2015/01/07 06:00 [entrez]
PHST- 2015/01/07 06:00 [pubmed]
PHST- 2015/05/12 06:00 [medline]
PHST- 2016/02/27 00:00 [pmc-release]
AID - S0021-9258(19)46834-8 [pii]
AID - M114.616714 [pii]
AID - 10.1074/jbc.M114.616714 [doi]
PST - ppublish
SO  - J Biol Chem. 2015 Feb 27;290(9):5592-605. doi: 10.1074/jbc.M114.616714. Epub 2015 
      Jan 5.