We examined the effects of the bioactive lipid, sphingosine, on the expression of the rate-limiting enzyme involved in surfactant phosphatidylcholine synthesis, CCTα (CTP:phosphocholine cytidylyltransferase α). Sphingosine decreased phosphatidylcholine synthesis by inhibiting CCT activity in primary alveolar type II epithelia. Sphingosine decreased CCTα protein and mRNA levels by approx. 50% compared with control. The bioactive lipid did not alter CCTα mRNA stability, but significantly inhibited its transcriptional rate. In murine lung epithelia, sphingosine selectively reduced CCTα promoter-reporter activity when transfected with a 2 kb CCTα promoter/luciferase gene construct. Sphingosine also decreased transgene expression in murine type II epithelia isolated from CCTα promoter-reporter transgenic mice harbouring this 2 kb proximal 5′-flanking sequence. Deletional analysis revealed that sphingosine responsiveness was mapped to a negative regulatory element contained within 814 bp upstream of the coding region. The results indicate that bioactive sphingolipid metabolites suppress surfactant lipid synthesis by inhibiting gene transcription of a key surfactant biosynthetic enzyme.
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Research Article|
August 24 2004
Transcriptional repression of the CTP:phosphocholine cytidylyltransferase gene by sphingosine
Alan J. RYAN;
Alan J. RYAN
*Department of Veterans Affairs Medical Center, University of Iowa College of Medicine, Iowa City, IA 52242, U.S.A.
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Kurt FISHER;
Kurt FISHER
†Departments of Internal Medicine and Biochemistry, University of Iowa College of Medicine, Iowa City, IA 52242, U.S.A.
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Christie P. THOMAS;
Christie P. THOMAS
†Departments of Internal Medicine and Biochemistry, University of Iowa College of Medicine, Iowa City, IA 52242, U.S.A.
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Rama K. MALLAMPALLI
Rama K. MALLAMPALLI
1
*Department of Veterans Affairs Medical Center, University of Iowa College of Medicine, Iowa City, IA 52242, U.S.A.
†Departments of Internal Medicine and Biochemistry, University of Iowa College of Medicine, Iowa City, IA 52242, U.S.A.
1To whom correspondence should be addressed, at Pulmonary and Critical Care Division, C-33K, GH, Departments of Internal Medicine and Biochemistry (email rama-mallampalli@uiowa.edu).
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Publisher: Portland Press Ltd
Received:
January 19 2004
Revision Received:
April 19 2004
Accepted:
May 13 2004
Accepted Manuscript online:
May 13 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2004
Biochem J (2004) 382 (2): 741–750.
Article history
Received:
January 19 2004
Revision Received:
April 19 2004
Accepted:
May 13 2004
Accepted Manuscript online:
May 13 2004
Citation
Alan J. RYAN, Kurt FISHER, Christie P. THOMAS, Rama K. MALLAMPALLI; Transcriptional repression of the CTP:phosphocholine cytidylyltransferase gene by sphingosine. Biochem J 1 September 2004; 382 (2): 741–750. doi: https://doi.org/10.1042/BJ20040105
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