Document Detail

Cloning of the human gene for intercellular adhesion molecule 1 and analysis of its 5'-regulatory region. Induction by cytokines and phorbol ester.
MedLine Citation:
PMID:  1680919     Owner:  NLM     Status:  MEDLINE    
Human intercellular adhesion molecule-1 (ICAM-1), a specific ligand for the lymphocyte function-associated Ag-1 (LFA-1), plays an important role in leukocyte-endothelial cell interactions. It is induced by proinflammatory cytokines such as IL-1, TNF-alpha, or IFN-gamma. However, little is known concerning the intracellular regulatory mechanisms which trigger ICAM-1 up-regulation. In order to study potential regulatory elements involved in ICAM-1 induction we have cloned the human ICAM-1 gene and 5 kb of its 5'-regulatory region. The sequence of the cDNA was found to be distributed over seven exons separated by six introns, whereby each of the five extracellular Ig-like domains of ICAM-1 is encoded by its own exon. The upstream sequence harbors a number of sequence motifs implicated in the regulation and expression of eukaryotic genes, including binding sites for the transcription factors SP-1, AP-1, and NF-kB. Primer extension and S1 nuclease analysis revealed two transcription initiation sites 319 bp and 41 bp upstream of the translation start site. Consensus TATA boxes were found at the expected positions about 25 bp upstream of both start sites. Reverse transcriptase polymerase chain reaction showed differential use of the two TATA boxes in A549 and HS913T cells. Both RNA seem to code for the same for of ICAM-1 protein. For regulation studies a 1.3-kb EcoRI/SalI fragment of the 5'-flanking region was used to promote transcription of a linked luciferase reporter gene in transient-transfection assays in A549 and HS913T cells. Treatment of A549 cells with IL-1 or TNF-alpha resulted in a two- or fourfold increase in luciferase activity. Furthermore, a sixfold induction could be achieved after treatment with the phorbol ester PMA. In contrast, agents that increase intracellular cAMP levels did not induce luciferase activity. Northern blot analysis was used to investigate the kinetics of ICAM-1 mRNA synthesis upon induction with TNF-alpha and PMA. These data suggest that the up-regulation of ICAM-1 by cytokines occurs at least partly at the transcriptional level. Deletion analysis of the 1.3-kb fragment of the 5'-flanking region revealed sequences responsible for promotion and inhibition of transcription. In particular, two functionally distinct regions have been characterized: a short fragment containing an NF-kB binding site has been shown to function as an activator, followed immediately downstream by a sequence acting as a silencer element. Therefore, ICAM-1 gene expression seems to be modulated by multiple cis-acting elements.
G Voraberger; R Schäfer; C Stratowa
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  147     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  1991 Oct 
Date Detail:
Created Date:  1991-11-18     Completed Date:  1991-11-18     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2777-86     Citation Subset:  AIM; IM    
Ernst Boehringer Institut, Bender & Co., Vienna, Austria.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/S59007;  S59308;  S59312;  S59314;  S59318;  S59363;  S59366;  X59286;  X59287;  X59288
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MeSH Terms
Base Sequence
Cell Adhesion Molecules / genetics*
Chromosome Deletion
Cloning, Molecular*
Dexamethasone / pharmacology
Gene Expression Regulation / drug effects*
Intercellular Adhesion Molecule-1
Interferon-gamma / pharmacology*
Interleukin-1 / pharmacology*
Molecular Sequence Data
Polymerase Chain Reaction
Promoter Regions, Genetic
Tetradecanoylphorbol Acetate / pharmacology*
Transcription, Genetic / drug effects
Tumor Necrosis Factor-alpha / pharmacology*
Reg. No./Substance:
0/Cell Adhesion Molecules; 0/Interleukin-1; 0/Tumor Necrosis Factor-alpha; 126547-89-5/Intercellular Adhesion Molecule-1; 16561-29-8/Tetradecanoylphorbol Acetate; 50-02-2/Dexamethasone; 82115-62-6/Interferon-gamma

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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