ABCMdb

ABCG1 p.Ser85Ala

Predicted by SNAP2:	A: N (53%), C: N (66%), D: D (71%), E: N (53%), F: N (53%), G: N (53%), H: N (72%), I: N (53%), K: N (57%), L: D (53%), M: D (66%), N: N (66%), P: D (59%), Q: N (61%), R: N (57%), T: N (97%), V: N (61%), W: D (75%), Y: N (57%),
Predicted by PROVEAN:	A: N, C: D, D: N, E: N, F: D, G: N, H: D, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, R: N, T: N, V: D, W: D, Y: D,

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[hide] Murine 12/15-lipoxygenase regulates ATP-binding ca... J Biol Chem. 2009 Nov 6;284(45):31303-14. Epub 2009 Aug 27. Nagelin MH, Srinivasan S, Nadler JL, Hedrick CC
Murine 12/15-lipoxygenase regulates ATP-binding cassette transporter G1 protein degradation through p38- and JNK2-dependent pathways.
J Biol Chem. 2009 Nov 6;284(45):31303-14. Epub 2009 Aug 27., 2009-11-06 [PMID:19713213]

Abstract [show]
12/15-Lipoxygenase (12/15LO) plays a role in the pathogenesis of atherosclerosis and diabetes and has been implicated in low density lipoprotein oxidation. Murine macrophages express high levels of 12/15LO and are key cells involved in the accumulation and efflux of oxidized low density lipoprotein in the arterial wall. During this process, macrophages up-regulate scavenger receptors that regulate lipid uptake, and ATP-binding cassette (ABC) transporters, that regulate lipid efflux. We have previously demonstrated that 12/15LO enhances the turnover and serine phosphorylation of ABCG1. In the current study, we further elucidate the mechanisms by which 12/15LO regulates ABCG1. Proteasomal inhibitors blocked the down-regulation of ABCG1 expression and resulted in accumulation of phosphorylated ABCG1. Macrophages that lack 12/15LO have enhanced transporter expression, reduced ABCG1 phosphorylation, and increased cholesterol efflux. Conversely, macrophages that overexpress 12/15LO have reduced ABCG1 expression, increased transporter phosphorylation, and reduced cholesterol efflux. 12/15LO plays a key role in activating the MAPK pathway. Inhibition of the p38 or JNK pathways with pharmacological inhibitors or dominant negative constructs blocked 12S-hydroxyeicosatetranoic acid-mediated degradation of ABCG1. Moreover, we isolated macrophages from JNK1-, JNK2-, and MKK3-deficient mice to analyze the involvement of specific MAPK pathways. JNK2- and MKK3-, but not JNK1-deficient macrophages were resistant to the down-regulation of ABCG1 protein, reduction in efflux, and increase in serine phosphorylation by 12S-hydroxyeicosatetranoic acid. These findings provide evidence that 12/15LO regulates ABCG1 expression and function through p38- and JNK2-dependent mechanisms, and that targeting these pathways may provide novel approaches for regulating cholesterol homeostasis.

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No. Sentence Comment
239 Sequentially, beginning at the N terminus, we changed serine residues Ser27, Ser-28, Ser-43, Ser-45, Ser-80, and Ser-85 to alanine residues. Login to comment
237 Sequentially, beginning at the N terminus, we changed serine residues Ser27, Ser-28, Ser-43, Ser-45, Ser-80, and Ser-85 to alanine residues. Login to comment