PMID- 23035115
OWN - NLM
STAT- MEDLINE
DCOM- 20130219
LR  - 20230815
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 47
DP  - 2012 Nov 16
TI  - Regulation of autophagy and its associated cell death by "sphingolipid rheostat": 
      reciprocal role of ceramide and sphingosine 1-phosphate in the mammalian target 
      of rapamycin pathway.
PG  - 39898-910
LID - 10.1074/jbc.M112.416552 [doi]
AB  - The role of "sphingolipid rheostat" by ceramide and sphingosine 1-phosphate (S1P) 
      in the regulation of autophagy remains unclear. In human leukemia HL-60 cells, 
      amino acid deprivation (AA(-)) caused autophagy with an increase in acid 
      sphingomyleinase (SMase) activity and ceramide, which serves as an autophagy 
      inducing lipid. Knockdown of acid SMase significantly suppressed the autophagy 
      induction. S1P treatment counteracted autophagy induction by AA(-) or 
      C(2)-ceramide. AA(-) treatment promoted mammalian target of rapamycin (mTOR) 
      dephosphorylation/inactivation, inducing autophagy. S1P treatment suppressed mTOR 
      inactivation and autophagy induction by AA(-). S1P exerts biological actions via 
      cell surface receptors, and S1P(3) among five S1P receptors was predominantly 
      expressed in HL-60 cells. We evaluated the involvement of S1P(3) in suppressing 
      autophagy induction. S1P treatment of CHO cells had no effects on mTOR 
      inactivation and autophagy induction by AA(-) or C(2)-ceramide. Whereas S1P 
      treatment of S1P(3) overexpressing CHO cells resulted in activation of the mTOR 
      pathway, preventing cells from undergoing autophagy induced by AA(-) or 
      C(2)-ceramide. These results indicate that S1P-S1P(3) plays a role in 
      counteracting ceramide signals that mediate mTOR-controlled autophagy. In 
      addition, we evaluated the involvement of ceramide-activated protein phosphatases 
      (CAPPs) in ceramide-dependent inactivation of the mTOR pathway. Inhibition of 
      CAPP by okadaic acid in AA(-)- or C(2)-ceramide-treated cells suppressed 
      dephosphorylation/inactivation of mTOR, autophagy induction, and 
      autophagy-associated cell death, indicating a novel role of ceramide-CAPPs in 
      autophagy induction. Moreover, S1P(3) engagement by S1P counteracted cell death. 
      Taken together, these results indicated that sphingolipid rheostat in 
      ceramide-CAPPs and S1P-S1P(3) signaling modulates autophagy and its associated 
      cell death through regulation of the mTOR pathway.
FAU - Taniguchi, Makoto
AU  - Taniguchi M
AD  - Division of Clinical Laboratory Medicine, Faculty of Medicine, Tottori 
      University, 86 Nishi-Machi, Yonago 683-8503, Japan.
FAU - Kitatani, Kazuyuki
AU  - Kitatani K
FAU - Kondo, Tadakazu
AU  - Kondo T
FAU - Hashimoto-Nishimura, Mayumi
AU  - Hashimoto-Nishimura M
FAU - Asano, Satoshi
AU  - Asano S
FAU - Hayashi, Akira
AU  - Hayashi A
FAU - Mitsutake, Susumu
AU  - Mitsutake S
FAU - Igarashi, Yasuyuki
AU  - Igarashi Y
FAU - Umehara, Hisanori
AU  - Umehara H
FAU - Takeya, Hiroyuki
AU  - Takeya H
FAU - Kigawa, Junzo
AU  - Kigawa J
FAU - Okazaki, Toshiro
AU  - Okazaki T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121003
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Ceramides)
RN  - 0 (Lysophospholipids)
RN  - 0 (N-acetylsphingosine)
RN  - 0 (Receptors, Lysosphingolipid)
RN  - 0 (ceramide 1-phosphate)
RN  - 26993-30-6 (sphingosine 1-phosphate)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.16 (Phosphoprotein Phosphatases)
RN  - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
RN  - NGZ37HRE42 (Sphingosine)
SB  - IM
MH  - Animals
MH  - Autophagy/*physiology
MH  - CHO Cells
MH  - Ceramides/genetics/*metabolism
MH  - Cricetinae
MH  - Cricetulus
MH  - Gene Knockdown Techniques
MH  - HL-60 Cells
MH  - Humans
MH  - Lysophospholipids/genetics/*metabolism
MH  - Phosphoprotein Phosphatases/genetics/metabolism
MH  - Phosphorylation/physiology
MH  - Receptors, Lysosphingolipid/genetics/metabolism
MH  - Signal Transduction/*physiology
MH  - Sphingomyelin Phosphodiesterase/genetics/metabolism
MH  - Sphingosine/*analogs & derivatives/genetics/metabolism
MH  - TOR Serine-Threonine Kinases/genetics/*metabolism
PMC - PMC3501064
EDAT- 2012/10/05 06:00
MHDA- 2013/02/21 06:00
PMCR- 2013/11/16
CRDT- 2012/10/05 06:00
PHST- 2012/10/05 06:00 [entrez]
PHST- 2012/10/05 06:00 [pubmed]
PHST- 2013/02/21 06:00 [medline]
PHST- 2013/11/16 00:00 [pmc-release]
AID - S0021-9258(20)62284-0 [pii]
AID - M112.416552 [pii]
AID - 10.1074/jbc.M112.416552 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 Nov 16;287(47):39898-910. doi: 10.1074/jbc.M112.416552. Epub 
      2012 Oct 3.