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PMID: 16997394 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

HNF4alpha and NF-E2 are key transcriptional regulators of the murine Abcc6 gene expression.

Biochimica et biophysica acta ·Vol. 1759 ·No. 8-9 ·2006-00-00 ·Pages 426-36

Douet V, VanWart CM, Heller MB, Reinhard S, Le Saux O

Abstract

Mutations in an ABC transporter gene called ABCC6 are responsible for pseudoxanthoma elasticum (PXE), a rare heritable disease characterized by elastic fiber calcification in skin, ocular and vascular tissues. The presumed function of this ABC transporter is to export metabolites from polarized cells. However, the endogenous substrate(s) are unknown and the exact relationship with elastic fibers is unclear. As ABCC6 is only expressed at high level in liver and kidneys, tissues seemingly unrelated to the PXE phenotype, we explored the transcriptional regulation of the murine Abcc6 gene to define the transcriptional signal conferring tissue specificity and to gather clues on its possible biological function. We cloned 2.9 kb of the mAbcc6 5'-flanking region and several deletion constructs linked to a luciferase reporter gene. We delineated a proximal promoter and a liver-specific enhancer region. We also demonstrated that the proximal region is a TATA-less promoter requiring an intact CCAAT-box and Sp1 binding for its basal activity. By using reporter assays and chromatin immunoprecipitations, we showed that HNF4alpha and surprisingly, NF-E2, enhanced the mAbcc6 promoter activity. The involvement of both HNF4alpha and NF-E2 in the mAbcc6 gene regulation suggests that Abcc6 might be involved in a detoxification processes related to hemoglobin or heme.

MeSH Terms
ATP-Binding Cassette Transporters/genetics Animals Base Sequence Cloning, Molecular DNA, Complementary/genetics Hepatocyte Nuclear Factor 4/metabolism Humans Mice Molecular Sequence Data Multidrug Resistance-Associated Proteins NF-E2 Transcription Factor, p45 Subunit/metabolism Promoter Regions, Genetic Transcriptional Activation
Chemicals
ATP-Binding Cassette Transporters Abcc6 protein, mouse DNA, Complementary Hepatocyte Nuclear Factor 4 Hnf4a protein, mouse Multidrug Resistance-Associated Proteins NF-E2 Transcription Factor, p45 Subunit Nfe2 protein, mouse
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Douet Vanessa
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, 651 Ilalo Street, BSB 222, Honolulu, HI 96813, USA.
VanWart Christopher M
Heller Matthew B
Reinhard Sabrina
Le Saux Olivier
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Article Info
Journal
Biochimica et biophysica acta
Abbr.
Biochim Biophys Acta
ISSN
0006-3002
DOI
10.1016/j.bbaexp.2006.08.002
Published
2006-00-00
Epub
2006-00-11
Pages
426-36
Language
English
Region
Netherlands
NLM ID
0217513
PMCID
PMC1876778
Subset
IM
Grants
NCRR NIH HHS · P20 RR016453 · United States
NCRR NIH HHS · RR16453 · United States
External Links
PubMed source DOI: 10.1016/j.bbaexp.2006.08.002 PMC Full Text
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