Disruption of an SP2/KLF6 repression complex by SHP is required for farnesoid X receptor-induced endothelial cell migration

Amitava Das, Martin E Fernandez-Zapico, Sheng Cao, Janet Yao, Stefano Fiorucci, Robert P. Hebbel, Raul Urrutia, Vijay Shah

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)39105-39113
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number51
DOIs
StatePublished - Dec 22 2006

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Endothelial cells
Matrix Metalloproteinase 9
Cell Movement
Endothelial Cells
Chromatin Immunoprecipitation
RNA Interference
Bile Acids and Salts
Chromatin
Assays
Homeostasis
Transcription Factors
Up-Regulation
Genes
Gels
Chemical activation
Cholesterol
RNA
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Disruption of an SP2/KLF6 repression complex by SHP is required for farnesoid X receptor-induced endothelial cell migration. / Das, Amitava; Fernandez-Zapico, Martin E; Cao, Sheng; Yao, Janet; Fiorucci, Stefano; Hebbel, Robert P.; Urrutia, Raul; Shah, Vijay.

In: Journal of Biological Chemistry, Vol. 281, No. 51, 22.12.2006, p. 39105-39113.

Research output: Contribution to journalArticle

Das, Amitava ; Fernandez-Zapico, Martin E ; Cao, Sheng ; Yao, Janet ; Fiorucci, Stefano ; Hebbel, Robert P. ; Urrutia, Raul ; Shah, Vijay. / Disruption of an SP2/KLF6 repression complex by SHP is required for farnesoid X receptor-induced endothelial cell migration. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 51. pp. 39105-39113.
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AU - Cao, Sheng

AU - Yao, Janet

AU - Fiorucci, Stefano

AU - Hebbel, Robert P.

AU - Urrutia, Raul

AU - Shah, Vijay

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AB - 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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