PMID- 16497721
OWN - NLM
STAT- MEDLINE
DCOM- 20060919
LR  - 20220129
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 15
IP  - 7
DP  - 2006 Apr 1
TI  - Rapamycin pre-treatment protects against apoptosis.
PG  - 1209-16
AB  - Macroautophagy (generally referred to as autophagy) mediates the bulk degradation 
      of cytoplasmic contents, including proteins and organelles, in lysosomes. 
      Rapamycin, a lipophilic, macrolide antibiotic, induces autophagy by inactivating 
      the protein mammalian target of rapamycin (mTOR). We previously showed that 
      rapamycin protects against mutant huntingtin-induced neurodegeneration in cell, 
      fly and mouse models of Huntington's disease [Ravikumar, B., Duden, R. and 
      Rubinsztein, D.C. (2002) Aggregate-prone proteins with polyglutamine and 
      polyalanine expansions are degraded by autophagy. Hum. Mol. Genet., 11, 
      1107-1117, Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, 
      L.G., Scaravilli, F., Easton, D.F., Duden, R., O'Kane, C.J. et al. (2004) 
      Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine 
      expansions in fly and mouse models of Huntington disease. Nat. Genet., 36, 
      585-595]. This protective effect of rapamycin was attributed to enhanced 
      clearance of the mutant protein via autophagy [Ravikumar, B., Duden, R. and 
      Rubinsztein, D.C. (2002) Aggregate-prone proteins with polyglutamine and 
      polyalanine expansions are degraded by autophagy. Hum. Mol. Genet., 11, 
      1107-1117, Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, 
      L.G., Scaravilli, F., Easton, D.F., Duden, R., O'Kane, C.J. et al. (2004) 
      Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine 
      expansions in fly and mouse models of Huntington disease. Nat. Genet., 36, 
      585-595]. Here, we show that rapamycin may have additional cytoprotective 
      effects--it protects cells against a range of subsequent pro-apoptotic insults 
      and reduces paraquat toxicity in Drosophila. This protection can be accounted for 
      by enhanced clearance of mitochondria by autophagy, thereby reducing cytosolic 
      cytochrome c release and downstream caspase activation after pro-apoptotic 
      insults. Thus, rapamycin (pro-autophagic) treatment may be useful in certain 
      disease conditions (including various neurodegenerative diseases) where a slow 
      but increased rate of apoptosis is evident, even if they are not associated with 
      overt aggregate formation.
FAU - Ravikumar, Brinda
AU  - Ravikumar B
AD  - Department of Medical Genetics, Cambridge Institute for Medical Research, 
      Wellcome/MRC Building, Cambridge, UK.
FAU - Berger, Zdenek
AU  - Berger Z
FAU - Vacher, Coralie
AU  - Vacher C
FAU - O'Kane, Cahir J
AU  - O'Kane CJ
FAU - Rubinsztein, David C
AU  - Rubinsztein DC
LA  - eng
GR  - G0000872/MRC_/Medical Research Council/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060223
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (CASP9 protein, human)
RN  - EC 3.4.22.- (Casp3 protein, mouse)
RN  - EC 3.4.22.- (Casp9 protein, mouse)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 9)
RN  - EC 3.4.22.- (Caspases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - *Apoptosis/drug effects
MH  - Autophagy
MH  - COS Cells
MH  - Caspase 3
MH  - Caspase 9
MH  - Caspases/metabolism
MH  - Cells, Cultured
MH  - Chlorocebus aethiops/metabolism
MH  - Cytochromes c/metabolism
MH  - Drosophila/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - Mitochondria/drug effects/metabolism
MH  - Sirolimus/metabolism/*pharmacology/toxicity
EDAT- 2006/02/25 09:00
MHDA- 2006/09/20 09:00
CRDT- 2006/02/25 09:00
PHST- 2006/02/25 09:00 [pubmed]
PHST- 2006/09/20 09:00 [medline]
PHST- 2006/02/25 09:00 [entrez]
AID - ddl036 [pii]
AID - 10.1093/hmg/ddl036 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2006 Apr 1;15(7):1209-16. doi: 10.1093/hmg/ddl036. Epub 2006 Feb 
      23.