Document Detail

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.
MedLine Citation:
PMID:  23035115     Owner:  NLM     Status:  MEDLINE    
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.
Makoto Taniguchi; Kazuyuki Kitatani; Tadakazu Kondo; Mayumi Hashimoto-Nishimura; Satoshi Asano; Akira Hayashi; Susumu Mitsutake; Yasuyuki Igarashi; Hisanori Umehara; Hiroyuki Takeya; Junzo Kigawa; Toshiro Okazaki
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-19     Completed Date:  2013-02-19     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  39898-910     Citation Subset:  IM    
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MeSH Terms
Autophagy / physiology*
CHO Cells
Ceramides / genetics,  metabolism*
Gene Knockdown Techniques
HL-60 Cells
Lysophospholipids / genetics,  metabolism*
Phosphoprotein Phosphatases / genetics,  metabolism
Phosphorylation / physiology
Receptors, Lysosphingolipid / genetics,  metabolism
Signal Transduction / physiology*
Sphingomyelin Phosphodiesterase / genetics,  metabolism
Sphingosine / analogs & derivatives*,  genetics,  metabolism
TOR Serine-Threonine Kinases / genetics,  metabolism*
Reg. No./Substance:
0/Ceramides; 0/Lysophospholipids; 0/N-acetylsphingosine; 0/Receptors, Lysosphingolipid; 0/ceramide 1-phosphate; 26993-30-6/sphingosine 1-phosphate; EC protein, human; EC Serine-Threonine Kinases; EC Phosphatases; EC Phosphodiesterase; NGZ37HRE42/Sphingosine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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