Transcriptional repression of the CTP:phosphocholine cytidylyltransferase gene by sphingosine

Alan J Ryan; Kurt Fisher; Christie P Thomas; Rama K Mallampalli

doi:10.1042/BJ20040105

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Transcriptional repression of the CTP:phosphocholine cytidylyltransferase gene by sphingosine

Journal article

Open access

Peer reviewed

Transcriptional repression of the CTP:phosphocholine cytidylyltransferase gene by sphingosine

Alan J Ryan, Kurt Fisher, Christie P Thomas and Rama K Mallampalli

Biochemical journal, Vol.382(Pt 2), pp.741-750

09/01/2004

DOI: 10.1042/BJ20040105

PMCID: PMC1133833

PMID: 15139854

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Abstract

We examined the effects of the bioactive lipid, sphingosine, on the expression of the rate-limiting enzyme involved in surfactant phosphatidylcholine synthesis, CCTalpha (CTP:phosphocholine cytidylyltransferase alpha). Sphingosine decreased phosphatidylcholine synthesis by inhibiting CCT activity in primary alveolar type II epithelia. Sphingosine decreased CCTalpha protein and mRNA levels by approx. 50% compared with control. The bioactive lipid did not alter CCTalpha mRNA stability, but significantly inhibited its transcriptional rate. In murine lung epithelia, sphingosine selectively reduced CCTalpha promoter-reporter activity when transfected with a 2 kb CCTalpha promoter/luciferase gene construct. Sphingosine also decreased transgene expression in murine type II epithelia isolated from CCTalpha 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.

Gene Expression Regulation, Enzymologic - drug effects

Transcription, Genetic - drug effects

Respiratory Mucosa - cytology

Respiratory Mucosa - enzymology

Rats

RNA, Messenger - metabolism

Pulmonary Alveoli - enzymology

Sphingosine - pharmacology

RNA, Messenger - biosynthesis

Enzyme Induction - genetics

Animals

Gene Expression Regulation, Enzymologic - genetics

Epithelial Cells - enzymology

Pulmonary Alveoli - cytology

Enzyme Induction - drug effects

Mice

Transcription, Genetic - genetics

Choline-Phosphate Cytidylyltransferase - genetics

Details

Title: Subtitle: Transcriptional repression of the CTP:phosphocholine cytidylyltransferase gene by sphingosine
Creators: Alan J Ryan - Department of Veterans Affairs Medical Center, University of Iowa College of Medicine, Iowa City, IA 52242, USA
Kurt Fisher
Christie P Thomas
Rama K Mallampalli
Resource Type: Journal article
Publication Details: Biochemical journal, Vol.382(Pt 2), pp.741-750
Publisher: England
DOI: 10.1042/BJ20040105
PMID: 15139854
PMCID: PMC1133833
ISSN: 0264-6021
eISSN: 1470-8728
Grant note: HL71040 / NHLBI NIH HHS R01 HL055584 / NHLBI NIH HHS R01 DK054348 / NIDDK NIH HHS HL55584 / NHLBI NIH HHS HL68135 / NHLBI NIH HHS R01 HL071040 / NHLBI NIH HHS DK54348 / NIDDK NIH HHS R01 HL068135 / NHLBI NIH HHS
Language: English
Date published: 09/01/2004
Academic Unit: Stead Family Department of Pediatrics; Obstetrics and Gynecology; Internal Medicine
Record Identifier: 9983986083902771

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