Disruption of an SP2/KLF6 repression complex by SHP is required for farnesoid X receptor-induced endothelial cell migration. J Biol Chem 2006 Dec 22;281(51):39105-13
Date
10/31/2006Pubmed ID
17071613DOI
10.1074/jbc.M607720200Scopus ID
2-s2.0-33846032701 (requires institutional sign-in at Scopus site) 66 CitationsAbstract
The farnesoid X receptor (FXR) signaling pathway regulates bile acid and cholesterol homeostasis. Here, we demonstrate, using a variety of gain- and loss-of-function approaches, a role of FXR in the process of cell motility, which involves the small heterodimeric partner (SHP)-dependent up-regulation of matrix metalloproteinase-9. We use this observation to reveal a transcriptional regulatory mechanism involving the SP/KLF transcription factors, SP2 and KLF6. Small interference RNA-based silencing studies in combination with promoter, gel shift, and chromatin immunoprecipitation assays indicate that SP2 and KLF6 bind to the matrix metalloproteinase-9 promoter and together function to maintain this gene in a silenced state. However, upon activation of FXR, SHP interacts with SP2 and KLF6, disrupting the SP2/KLF6 repressor complex. Thus, together, these studies identify a mechanism for antagonizing Sp/KLF protein repression function via SHP, with this process regulating endothelial cell motility.
Author List
Das A, Fernandez-Zapico ME, Cao S, Yao J, Fiorucci S, Hebbel RP, Urrutia R, Shah VHAuthor
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cell MovementDNA-Binding Proteins
Endothelial Cells
Gene Expression Regulation
Gene Silencing
Humans
Kruppel-Like Factor 6
Kruppel-Like Transcription Factors
Matrix Metalloproteinase 9
Models, Biological
Oligonucleotide Array Sequence Analysis
Proto-Oncogene Proteins
RNA, Small Interfering
Receptors, Cytoplasmic and Nuclear
Signal Transduction
Sp1 Transcription Factor
Transcription Factors
Transcription, Genetic