Distinct Role of Kruppel-like Factor 11 in the Regulation of Prostaglandin E2 Biosynthesis

Kenneth K Wang,Gwen Lomberk,Navtej S Buttar,Shalini Achra,Martin E Fernandez-Zapico,Juliana Bonilla-Velez,Sumera I Ilyas,Raul Urrutia,Cathrine J Demars,Shahrooz Rashtak

doi:10.1074/jbc.m109.077065

Kenneth K Wang, Gwen Lomberk + Show 8 more

Open Access

https://doi.org/10.1074/jbc.m109.077065

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Abstract

Kruppel-like factor (KLF) proteins are emerging as key regulators of lipid metabolism, diabetes, and the biosynthesis of immunological cytokines. However, their role in the synthesis of prostaglandins, widely known biochemical mediators that act in a myriad of cell biological processes remain poorly understood. Consequently, in this study a comprehensive investigation at the cellular, biochemical, and molecular levels reveal that KLF11 inhibits prostaglandin E(2) synthesis via transcriptional silencing of the promoter of its biosynthetic enzyme, cytosolic phospholipase A2alpha. Mechanistically, KLF11 accomplishes this function by binding to the promoter via specific GC-rich sites and recruiting the Sin3-histone deacetylase chromatin remodeling complex. Further functional characterization reveals that this function of KLF11 can be reversed by epidermal growth factor receptor-AKT-mediated post-translational modification of threonine 56, a residue within its Sin3-binding domain. This is the first evidence supporting a relevant role for any KLF protein in doing both: transcriptionally inhibiting prostaglandin biosynthesis and its reversibility by an epidermal growth factor receptor-AKT signaling-mediated posttranslational mechanisms.

Highlights

The regulation of the PGE2 synthesis pathway can be divided into three main steps, in which a key step involves the mobilization of arachidonic acid from membrane phospholipids by the action of phospholipase enzymes (2–5)
KLF11 Represses the Rate-limiting Enzyme cPLA2␣ and Downregulates PGE2 Synthesis—As mentioned, cPLA2␣ is a rate-limiting enzyme involved in the regulation of PGE2 synthesis (3, 11, 44, 45) and because PGE2 plays a direct role in important biochemical processes and pathological states (13, 15, 23, 28, 31, 36, 46–50), a tight regulation of this pathway is of paramount importance for homeostasis and diseases
Co-transfection with KLF11 decreased cPLA2␣ promoter activity in three different cancer cell lines, namely in FLO cells (66 Ϯ 3.3%), SEG-1 (54.4 Ϯ 5.8%), and SKGT-4 (p Ͻ 0.05, Fig. 1B). This KLF11mediated inhibition of cPLA2␣ promoter activity was associated with decreased cPLA2␣ mRNA expression in all three cell lines (Fig. 1C)

Summary

Introduction

The regulation of the PGE2 synthesis pathway can be divided into three main steps, in which a key step involves the mobilization of arachidonic acid from membrane phospholipids by the action of phospholipase enzymes (2–5). Co-transfection with KLF11 decreased cPLA2␣ promoter activity in three different cancer cell lines, namely in FLO cells (66 Ϯ 3.3%), SEG-1 (54.4 Ϯ 5.8%), and SKGT-4 (by 45 Ϯ 9%) (p Ͻ 0.05, Fig. 1B). These results demonstrate that KLF11 represses both cPLA2␣ promoter and enzyme activity it decreases PGE2 production.

Results

Conclusion