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https://hdl.handle.net/2440/63808
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Type: | Journal article |
Title: | The Sphingosine Kinase 1 Inhibitor 2-(p-Hydroxyanilino)-4-(p-chlorophenyl)thiazole Induces Proteasomal Degradation of Sphingosine Kinase 1 in Mammalian Cells |
Author: | Tonelli, F. Loveridge, C. Leclercq, T. Lim, K. Long, J. Berdyshev, E. Tate, R. Natarajan, V. Pitson, S. Pyne, N. Pyne, S. |
Citation: | Journal of Biological Chemistry, 2010; 285(50):38841-38852 |
Publisher: | Amer Soc Biochemistry Molecular Biology Inc |
Issue Date: | 2010 |
ISSN: | 0021-9258 1083-351X |
Statement of Responsibility: | Carolyn Loveridge, Francesca Tonelli, Tamara Leclercq, Keng Gat Lim, Jaclyn S. Long, Evgeny Berdyshev, Rothwelle J. Tate, Viswanathan Natarajan, Stuart M. Pitson, Nigel J. Pyne and Susan Pyne |
Abstract: | Sphingosine kinase 1 (SK1) is an enzyme that catalyzes the phosphorylation of sphingosine to produce the bioactive lipid sphingosine 1-phosphate (S1P). We demonstrate here that the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of SK1 in human pulmonary artery smooth muscle cells, androgen-sensitive LNCaP prostate cancer cells, MCF-7 and MCF-7 HER2 breast cancer cells and that this is likely mediated by ceramide as a consequence of catalytic inhibition of SK1 by SKi. Moreover, SK1 is polyubiquitinated under basal conditions, and SKi appears to increase the degradation of SK1 by activating the proteasome. In addition, the proteasomal degradation of SK1a and SK1b in androgen-sensitive LNCaP cells is associated with the induction of apoptosis. However, SK1b in LNCaP-AI cells (androgen-independent) is less sensitive to SKi-induced proteasomal degradation and these cells are resistant to SKi-induced apoptosis, thereby implicating the ubiquitin-proteasomal degradation of SK1 as an important mechanism controlling cell survival. |
Keywords: | Cell Line, Tumor Humans Breast Neoplasms Prostatic Neoplasms Thiazoles Proteasome Endopeptidase Complex Phosphotransferases (Alcohol Group Acceptor) Ubiquitin Densitometry Apoptosis Cell Survival Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Female Male |
Rights: | © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. |
DOI: | 10.1074/jbc.M110.127993 |
Published version: | http://dx.doi.org/10.1074/jbc.m110.127993 |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
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