Disruption of an SP2/KLF6 repression complex by SHP is required for farnesoid X receptor-induced endothelial cell migration.
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.
Das
Amitava
A
Gastroenterology Research Unit, Department of Physiology and Cancer Cell Biology Program, Mayo Clinic, Rochester, Minnesota 55905, USA. das.amitava@mayo.edu
Fernandez-Zapico
Martin E
ME
Cao
Sheng
S
Yao
Janet
J
Fiorucci
Stefano
S
Hebbel
Robert P
RP
Urrutia
Raul
R
Shah
Vijay H
VH
D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000737:chemistry*; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry*; D014158:Transcription, Genetic; D000099150:Receptor, Farnesoid X-Activated
D004268:DNA-Binding Proteins; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D020780:Matrix Metalloproteinase 9; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C105465:KLF6 protein, human