Relaxin activates peroxisome proliferator-activated receptor γ(PPAR γ)through a pathway involving PPAR γ coactivator 1α (PGC1α)

Sudhir Singh, Ronda L. Simpson, Robert G Bennett

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Relaxin activation of its receptor RXFP1 triggers multiple signaling pathways. Previously, we have shown that relaxin activates &gamma transcriptional activity in a ligand-independent manner, but the mechanism for this effect was unknown. In this study, we examined the signaling pathways of downstream of RXFP1 leading to γ activation. Using cells stably expressing RXFP1, we found that relaxin regulation of &gamma activity requires accumulation of cAMP and subsequent activation of cAMP-dependent protein kinase (PKA). The activated PKA subsequently phosphorylated cAMP response element-binding protein (CREB) at Ser-133 to activate it directly, as well as indirectly through mitogen activated protein kinase p38 MAPK. Activated CREB was required for relaxin stimulation of &gamma activity, while there was no evidence for a role of the nitric oxide or ERK MAPK pathways. Relaxin increased the mRNA and protein levels of the coactivator protein PGC1α, and this effect was dependent on PKA, and was completely abrogated by a domi-nant-negative form of CREB. This mechanism was confirmed in a hepatic stellate cell line stably that endogenously expresses RXFP1. Reduction of PGC1α levels using siRNA diminished the regulation of γα by relaxin. These results suggest that relaxin activates the cAMP/PKA and p38 MAPK pathways to phosphorylate CREB, resulting in increased PGC1αlevels. This provides a mechanism for the ligand-independent activation of &gamma in response to relaxin.

Original languageEnglish (US)
Pages (from-to)950-959
Number of pages10
JournalJournal of Biological Chemistry
Volume290
Issue number2
DOIs
StatePublished - Jan 9 2015

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Relaxin
Peroxisome Proliferator-Activated Receptors
Cyclic AMP Response Element-Binding Protein
p38 Mitogen-Activated Protein Kinases
Chemical activation
Protein Kinases
Ligands
Hepatic Stellate Cells
MAP Kinase Signaling System
Cyclic AMP-Dependent Protein Kinases
Small Interfering RNA
Nitric Oxide
Proteins
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Relaxin activates peroxisome proliferator-activated receptor γ(PPAR γ)through a pathway involving PPAR γ coactivator 1α (PGC1α). / Singh, Sudhir; Simpson, Ronda L.; Bennett, Robert G.

In: Journal of Biological Chemistry, Vol. 290, No. 2, 09.01.2015, p. 950-959.

Research output: Contribution to journalArticle

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