Transcriptional regulation of lysosomal acid lipase in differentiating monocytes is mediated by transcription factors Sp1 and AP-2.

Abstract

Human lysosomal acid lipase (LAL) is a hydrolase required for the cleavage of cholesteryl esters and triglycerides derived from plasma lipoproteins. It is shown here that during monocyte to macrophage differentiation, the expression of LAL-mRNA is induced. This induction is dependent on protein kinase C activity and protein synthesis. The cell type-specific increase in LAL expression is further investigated in the THP-1 cell line with respect to transcriptional regulation. The human monocytic leukemia cell line THP-1 differentiates into macrophage-like cells when treated with phorbol esters. In order to determine the cis-acting elements necessary for both basal and phorbol 12-myristate-13 acetate (PMA)-enhanced promoter activity, we performed deletion analysis and reporter gene assays. A PMA responsive element has been identified between -182 bp and -107 bp upstream of the major transcription start site. Gel mobility shift assays demonstrated that binding of Sp1 and AP-2 to the LAL promoter is increased by PMA in THP-1 cells. Co-transfections with expression plasmids for Sp1 and AP-2 further emphasized the important role of these transcription factors in both basal and PMA-enhanced LAL expression. Our data suggest that differentiation dependent increase of lysosomal acid lipase (LAL) expression in THP-1 cells is mediated by a concerted action of Sp1 and AP-2.

• Authors: S Ries, C Büchler, T Langmann, P Fehringer, C Aslanidis, G Schmitz
• Journal: Journal of lipid research (J Lipid Res) Vol. 39 Issue 11 Pg. 2125-34 (Nov 1998) ISSN: 0022-2275 [Print] United States
• PMID: 9799798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• RNA, Messenger
• Sp1 Transcription Factor
• Transcription Factor AP-2
• Transcription Factors
• Protein Kinase C
• Sterol Esterase
• Tetradecanoylphorbol Acetate

Topics

• Cell Differentiation (drug effects)
• Cell Line
• Chromosome Mapping
• DNA-Binding Proteins (physiology)
• Enzyme Activation
• Gene Expression Regulation, Enzymologic
• Humans
• Macrophages (cytology, drug effects, enzymology)
• Monocytes (cytology, drug effects, enzymology)
• Promoter Regions, Genetic
• Protein Kinase C (metabolism)
• Protein Processing, Post-Translational
• RNA, Messenger (metabolism)
• Sp1 Transcription Factor (physiology)
• Sterol Esterase (biosynthesis, genetics)
• Tetradecanoylphorbol Acetate (pharmacology)
• Transcription Factor AP-2
• Transcription Factors (physiology)
• Transcription, Genetic
• Up-Regulation