Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated upregulation of ... View Full Text


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Article Info

DATE

2013-11-21

AUTHORS

C Rutherford, S Childs, J Ohotski, L McGlynn, M Riddick, S MacFarlane, D Tasker, S Pyne, N J Pyne, J Edwards, T M Palmer

ABSTRACT

Although the ability of bioactive lipid sphingosine-1-phosphate (S1P) to positively regulate anti-apoptotic/pro-survival responses by binding to S1P1 is well known, the molecular mechanisms remain unclear. Here we demonstrate that expression of S1P1 renders CCL39 lung fibroblasts resistant to apoptosis following growth factor withdrawal. Resistance to apoptosis was associated with attenuated accumulation of pro-apoptotic BH3-only protein Bim. However, although blockade of extracellular signal-regulated kinase (ERK) activation could reverse S1P1-mediated suppression of Bim accumulation, inhibition of caspase-3 cleavage was unaffected. Instead S1P1-mediated inhibition of caspase-3 cleavage was reversed by inhibition of phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC), which had no effect on S1P1 regulation of Bim. However, S1P1 suppression of caspase-3 was associated with increased expression of anti-apoptotic protein Mcl-1, the expression of which was also reduced by inhibition of PI3K and PKC. A role for the induction of Mcl-1 in regulating endogenous S1P receptor-dependent pro-survival responses in human umbilical vein endothelial cells was confirmed using S1P receptor agonist FTY720-phosphate (FTY720P). FTY720P induced a transient accumulation of Mcl-1 that was associated with a delayed onset of caspase-3 cleavage following growth factor withdrawal, whereas Mcl-1 knockdown was sufficient to enhance caspase-3 cleavage even in the presence of FTY720P. Consistent with a pro-survival role of S1P1 in disease, analysis of tissue microarrays from ER+ breast cancer patients revealed a significant correlation between S1P1 expression and tumour cell survival. In these tumours, S1P1 expression and cancer cell survival were correlated with increased activation of ERK, but not the PI3K/PKB pathway. In summary, pro-survival/anti-apoptotic signalling from S1P1 is intimately linked to its ability to promote the accumulation of pro-survival protein Mcl-1 and downregulation of pro-apoptotic BH3-only protein Bim via distinct signalling pathways. However, the functional importance of each pathway is dependent on the specific cellular context. More... »

PAGES

e927-e927

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/cddis.2013.455

DOI

http://dx.doi.org/10.1038/cddis.2013.455

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24263101


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31 schema:description Although the ability of bioactive lipid sphingosine-1-phosphate (S1P) to positively regulate anti-apoptotic/pro-survival responses by binding to S1P1 is well known, the molecular mechanisms remain unclear. Here we demonstrate that expression of S1P1 renders CCL39 lung fibroblasts resistant to apoptosis following growth factor withdrawal. Resistance to apoptosis was associated with attenuated accumulation of pro-apoptotic BH3-only protein Bim. However, although blockade of extracellular signal-regulated kinase (ERK) activation could reverse S1P1-mediated suppression of Bim accumulation, inhibition of caspase-3 cleavage was unaffected. Instead S1P1-mediated inhibition of caspase-3 cleavage was reversed by inhibition of phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC), which had no effect on S1P1 regulation of Bim. However, S1P1 suppression of caspase-3 was associated with increased expression of anti-apoptotic protein Mcl-1, the expression of which was also reduced by inhibition of PI3K and PKC. A role for the induction of Mcl-1 in regulating endogenous S1P receptor-dependent pro-survival responses in human umbilical vein endothelial cells was confirmed using S1P receptor agonist FTY720-phosphate (FTY720P). FTY720P induced a transient accumulation of Mcl-1 that was associated with a delayed onset of caspase-3 cleavage following growth factor withdrawal, whereas Mcl-1 knockdown was sufficient to enhance caspase-3 cleavage even in the presence of FTY720P. Consistent with a pro-survival role of S1P1 in disease, analysis of tissue microarrays from ER+ breast cancer patients revealed a significant correlation between S1P1 expression and tumour cell survival. In these tumours, S1P1 expression and cancer cell survival were correlated with increased activation of ERK, but not the PI3K/PKB pathway. In summary, pro-survival/anti-apoptotic signalling from S1P1 is intimately linked to its ability to promote the accumulation of pro-survival protein Mcl-1 and downregulation of pro-apoptotic BH3-only protein Bim via distinct signalling pathways. However, the functional importance of each pathway is dependent on the specific cellular context.
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37 schema:keywords BH3
38 BIM
39 Bim accumulation
40 ERK
41 FTY720-phosphate
42 FTY720P
43 FTY720P.
44 Mcl-1
45 Mcl-1 knockdown
46 PI3K
47 PI3K/PKB pathway
48 PKB pathway
49 S1P1
50 S1P1 expression
51 ability
52 accumulation
53 activation
54 analysis
55 anti-apoptotic protein Mcl-1
56 anti-apoptotic signaling
57 apoptosis
58 attenuated accumulation
59 bioactive lipids
60 blockade
61 breast cancer patients
62 cancer cell survival
63 cancer patients
64 caspase-3
65 caspase-3 cleavage
66 cell survival
67 cells
68 cellular context
69 cleavage
70 context
71 correlation
72 disease
73 distinct signaling pathways
74 downregulation
75 effect
76 endothelial cells
77 expression
78 extracellular signal-regulated kinase (ERK) activation
79 factor withdrawal
80 functional importance
81 growth factor withdrawal
82 human umbilical vein endothelial cells
83 importance
84 increased activation
85 induction
86 inhibition
87 kinase C
88 kinase activation
89 knockdown
90 lipids
91 lung
92 mechanism
93 microarray
94 molecular mechanisms
95 onset
96 pathway
97 patients
98 presence
99 pro-apoptotic BH3
100 pro-survival protein Mcl-1
101 pro-survival response
102 pro-survival role
103 protein Bim
104 protein Mcl-1
105 protein kinase C
106 receptors
107 regulation
108 resistance
109 response
110 role
111 signal-regulated kinase activation
112 signaling
113 signaling pathways
114 significant correlation
115 specific cellular context
116 sphingosine-1-phosphate receptors
117 summary
118 suppression
119 survival
120 tissue microarray
121 transient accumulation
122 tumor cell survival
123 tumors
124 umbilical vein endothelial cells
125 upregulation
126 vein endothelial cells
127 withdrawal
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