PMID- 24366666
OWN - NLM
STAT- MEDLINE
DCOM- 20140401
LR  - 20231213
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 85
IP  - 3
DP  - 2014 Mar
TI  - cdc-like/dual-specificity tyrosine phosphorylation-regulated kinases inhibitor 
      leucettine L41 induces mTOR-dependent autophagy: implication for Alzheimer's 
      disease.
PG  - 441-50
LID - 10.1124/mol.113.090837 [doi]
AB  - Leucettines, a family of pharmacological inhibitors of dual-specificity tyrosine 
      phosphorylation regulated kinases and cdc-like kinases (CLKs), are currently 
      under investigation for their potential therapeutic application to Down syndrome 
      and Alzheimer's disease. We here report that leucettine L41 triggers bona fide 
      autophagy in osteosarcoma U-2 OS cells and immortalized mouse hippocampal HT22 
      cells, characterized by microtubule-associated protein light chain 3 membrane 
      translocation and foci formation. Leucettine L41-triggered autophagy requires the 
      Unc-51-like kinase and is sensitive to the phosphatidylinositol 3-kinase (PI3K) 
      inhibitors wortmannin and 3-methyladenine, suggesting that it acts through the 
      mammalian target of rapamycin (mTOR)/PI3K-dependent pathway. Leucettine L41 does 
      not act by modifying the autophagic flux of vesicles. Leucettine L41-induced 
      autophagy correlates best with inhibition of CLKs. Leucettine L41 modestly 
      inhibited phosphatidylinositol-3-phosphate 5-kinase, FYVE domain-containing 
      activity as tested both in vitro and in vivo, which may also contribute to 
      autophagy induction. Altogether these results demonstrate that leucettines can 
      activate the autophagic mTOR/PI3K pathway, a characteristic that may turn 
      advantageous in the context of Alzheimer's disease treatment.
FAU - Fant, Xavier
AU  - Fant X
AD  - Centre National de la Recherche Scientifique (CNRS), USR3151, "Protein 
      Phosphorylation and Human Disease," Station Biologique, Roscoff cedex, France 
      (X.F., E.D.); Institut National de la Sante et de la Recherche 
      Medicale/Universite Paul Sabatier Unite Mixte de Recherche (UMR) 1048, 
      "Production et fonctions plaquettaires: signalisation et phosphoinositides" 
      group, Institut des Maladies Metaboliques et Cardiovasculaires (I2MC), Toulouse 
      cedex, France (G.C., B.P.); Department of Physiology, Wayne State University 
      School of Medicine, Detroit, Michigan (D.S., A.S.); Laboratoire Sciences 
      Chimiques de Rennes, UMR CNRS 6226, Groupe Ingenierie Chimique et Molecules pour 
      le Vivant (ICMV), Universite de Rennes, Campus de Beaulieu, Rennes cedex, France 
      (E.L., F.C., J.-P.B.); and ManRos Therapeutics, Perharidy Research Center, 
      Roscoff, Bretagne, France (L.M.).
FAU - Durieu, Emilie
AU  - Durieu E
FAU - Chicanne, Gaetan
AU  - Chicanne G
FAU - Payrastre, Bernard
AU  - Payrastre B
FAU - Sbrissa, Diego
AU  - Sbrissa D
FAU - Shisheva, Assia
AU  - Shisheva A
FAU - Limanton, Emmanuelle
AU  - Limanton E
FAU - Carreaux, Francois
AU  - Carreaux F
FAU - Bazureau, Jean-Pierre
AU  - Bazureau JP
FAU - Meijer, Laurent
AU  - Meijer L
LA  - eng
GR  - R01 DK058058/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131223
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 
      (((5Z)5-(1,3-benzodioxol-5-yl)methylene-2-phenylamino-3,5-dihydro-4H-imidazol-4-one))
RN  - 0 (Dioxoles)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Alzheimer Disease/*drug therapy/genetics/metabolism
MH  - Animals
MH  - Autophagy/*drug effects/genetics/immunology
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Dioxoles/*pharmacology
MH  - Enzyme Inhibitors/*pharmacology
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Mice
MH  - Microtubule-Associated Proteins/genetics/metabolism
MH  - Osteosarcoma/drug therapy/genetics/metabolism
MH  - Phosphatidylinositol 3-Kinases/genetics/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/*drug effects/genetics/immunology
MH  - Protein Serine-Threonine Kinases/genetics/metabolism
MH  - Protein-Tyrosine Kinases/genetics/metabolism
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
MH  - Tyrosine/genetics/*metabolism
MH  - Dyrk Kinases
PMC - PMC6067634
EDAT- 2013/12/25 06:00
MHDA- 2014/04/02 06:00
PMCR- 2014/03/01
CRDT- 2013/12/25 06:00
PHST- 2013/12/25 06:00 [entrez]
PHST- 2013/12/25 06:00 [pubmed]
PHST- 2014/04/02 06:00 [medline]
PHST- 2014/03/01 00:00 [pmc-release]
AID - mol.113.090837 [pii]
AID - MOL_090837 [pii]
AID - 10.1124/mol.113.090837 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2014 Mar;85(3):441-50. doi: 10.1124/mol.113.090837. Epub 2013 Dec 
      23.