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PMID: 16488890 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Human prolyl-4-hydroxylase alpha(I) transcription is mediated by upstream stimulatory factors.

The Journal of biological chemistry ·Vol. 281 ·No. 16 ·2006-04-21 ·Pages 10849-55

Chen L, Shen YH, Wang X, Wang J, Gan Y, Chen N, Wang J, LeMaire SA, Coselli JS, Wang XL

Abstract

Prolyl-4-hydroxylase alpha(I) (P4Halpha(I)) is the rate-limiting subunit for P4H enzyme activity, which is essential for procollagen hydroxylation and secretion. In the current study, we have characterized the human P4Halpha(I) promoter for transcription factors and DNA elements regulating P4Halpha(I) expression. Using a progressive deletion cloning approach, we have constructed pGL3-P4Halpha(I) recombinant plasmids. We have identified a positive regulatory region at the positions of bp -184 to -97 responsible for approximately 80% of the P4Halpha(I) promoter efficiency. Three E-boxes were located within this region, and the E-box at position bp -135 explains most of the regulatory capacity. Upstream stimulatory factors (USF1/USF2) were shown to bind on the E-box using chromatin immunoprecipitation assay. Suppression of USF1 and/or USF2 using specific short interference RNA resulted in a significant reduction in P4Halpha(I) promoter activity, and overexpressed USF1 or USF2 increased P4Halpha(I) promoter activity significantly. Although transforming growth factor beta1 increased the USF1/USF2-E-box binding and P4Halpha(I) promoter activity, this up-regulatory effect can be largely prevented by USF1/USF2-specific short interference RNA. On the other hand, cigarette smoking extracts, which have been shown to suppress P4Halpha(I) expression, inhibited the binding between the USF1/USF2 and E-box, resulting in a reduced P4Halpha(I) promoter activity. Furthermore, the E-box on the P4Halpha(I) promoter appeared to indiscriminately bind with either USF1 or USF2, with a similar outcome on the promoter efficiency. In conclusion, our study shows that USF1/USF2 plays a critical role in basal P4Halpha(I) expression, and both positive (transforming growth factor beta1) and negative (cigarette smoking extract) regulators appear to influence the USF-E-box interaction and affect P4Halpha(I) expression.

MeSH Terms
Base Sequence Binding Sites Chromatin Immunoprecipitation DNA/genetics DNA Primers/chemistry DNA-Binding Proteins/chemistry Down-Regulation Gene Expression Regulation HeLa Cells Humans Luciferases/metabolism Models, Genetic Molecular Sequence Data Plasmids/metabolism Procollagen-Proline Dioxygenase/biosynthesis,chemistry,genetics Promoter Regions, Genetic RNA, Messenger/metabolism RNA, Small Interfering/metabolism Response Elements Smoking Transcription Factors/metabolism Transcription, Genetic Transfection Transforming Growth Factor beta/metabolism Transforming Growth Factor beta1 Up-Regulation
Chemicals
DNA Primers DNA-Binding Proteins RNA, Messenger RNA, Small Interfering TGFB1 protein, human Transcription Factors Transforming Growth Factor beta Transforming Growth Factor beta1 DNA Luciferases P4HA1 protein, human Procollagen-Proline Dioxygenase
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Chen Li
Section of Adult Cardiothoracic Service, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas 77030, USA.
Shen Ying H
Wang Xinwen
Wang Jing
Gan Yehua
Chen Nanyue
Wang Jian
LeMaire Scott A
Coselli Joseph S
Wang Xing Li
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M511237200
Published
2006-04-21
Epub
2006-00-17
Pages
10849-55
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2819823
Subset
IM
Grants
NHLBI NIH HHS · R01 HL066053 · United States
NHLBI NIH HHS · K08 HL080085-02 · United States
NHLBI NIH HHS · K08 HL080085 · United States
NHLBI NIH HHS · HL066053 · United States
NHLBI NIH HHS · HL71608 · United States
NHLBI NIH HHS · R01 HL071608 · United States
External Links
PubMed source DOI: 10.1074/jbc.M511237200 PMC Full Text View journal details
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