Regulation of Platelet-derived Growth Factor-A Chain by Krüppel-like Factor 5 : NEW PATHWAY OF COOPERATIVE ACTIVATION WITH NUCLEAR FACTOR-κB

Kenichi Aizawa,Toru Suzuki,Nanae Kada,Atsushi Ishihara,Keiko Kawai-Kowase,Takayoshi Matsumura,Kana Sasaki,Yoshiko Munemasa,Ichiro Manabe,Masahiko Kurabayashi,Tucker Collins,Ryozo Nagai

doi:10.1074/jbc.m306621200

Abstract

The transcription factor Krüppel-like factor 5 (KLF5) and its genetically downstream target gene platelet-derived growth factor-A (PDGF-A) chain are key factors in regulation of cardiovascular remodeling in response to stress. We show that KLF5 mediates a novel distinct delayed persistent induction of PDGF-A chain in response to the model agonist, phorbol ester, through a cis-element previously shown to mediate phorbol ester induction on to PDGF-A chain through the early growth response factor (Egr-1). Interestingly, the nuclear factor-kappaB (NF-kappaB) p50 subunit further cooperatively activates PDGF-A chain through protein-protein interaction with KLF5 but not Egr-1. RNA interference analysis confirmed that KLF5 and p50 are important for induction of PDGF-A chain. Collectively, we identify a novel regulatory pathway in which PDGF-A chain gene expression, under the control of KLF5, is cooperatively activated by the NF-kappaB p50 subunit and a pathophysiological stimulus.

Highlights

The transcription factor Kruppel-like factor 5 (KLF5) and its genetically downstream target gene platelet-derived growth factor-A (PDGF-A) chain are key factors in regulation of cardiovascular remodeling in response to stress
New Pathway of Regulation of PDGF-A Chain Induction by KLF5—The present study shows that KLF5 transcriptionally regulates the PDGF-A chain with cooperative activation by phorbol ester
Forced expression of KLF5 in combination with phorbol ester administration was sufficient to induce PDGF-A chain expression in the cell, which strongly suggests that this combination of factors is relevant in the pathophysiological situation

Summary

Introduction

The transcription factor Kruppel-like factor 5 (KLF5) and its genetically downstream target gene platelet-derived growth factor-A (PDGF-A) chain are key factors in regulation of cardiovascular remodeling in response to stress. Using reporter constructs harboring the PDGF-A chain promoter upstream of a luciferase reporter, cell co-transfection studies showed that KLF5 activates the PDGF-A chain promoter (containing 900 bp upstream of the transcription initiation site) (Fig. 1, A and B).

Results

Conclusion