Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 51, Pages 39105-39113Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M607720200
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Funding
- NCI NIH HHS [P50 CA102701] Funding Source: Medline
- NHLBI NIH HHS [P01-HL076540, P01 HL055552] Funding Source: Medline
- NIDDK NIH HHS [R01 DK052913-08, R01 DK059615, R01 DK052913-09, R01 DK052913, DK 52913] Funding Source: Medline
- PHS HHS [R01-59388, R01-59615] Funding Source: Medline
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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.
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