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 A2␣. 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.
Prostaglandin E 2 (PGE 2 )2 biosynthesis pathway is strongly implicated in wide-ranging physiological and pathological events, such as ovulation, implantation, and parturition during reproduction; ductus arteriosus closure in neonates; pain hypersensitivity, inflammation, febrile response, gastric mucosal protection, T cell differentiation and repair during acute or chronic injury; cell proliferation, neoplastic transformation, and invasion during carcinogenesis as well as alteration in kidney function, vascular tone, bone resorption, and neurological disorders like Alzheimer disease. Therefore expanding our understanding of regulation of PGE 2 biosynthesis has unique biochemical and cellular relevance (1).The regulation of the PGE 2 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). Among many phospholipases, the cytosolic phospholipase A2␣ (cPLA2␣) has very high substrate specificity toward arachidonic acid, and therefore is the key regulator of intracellular arachidonic acid release (2-6). The mobilization of arachidonic acid is generally considered the rate-limiting step in the synthesis of PGE 2 (4). Subsequent steps in the PGE 2 synthesis pathway involve the alignment of COX-2 and microsomal PGE 2 synthase, which convert intracellular arachidonic acid to a prostaglandin intermediate and finally PGE 2 (7-9). The intracellular release of arachidonic acid, which occurs via cPLA2␣, favors COX-2 and microsomal PGE 2 synthase to synthesize PGE 2 instead of other prostaglandins (8 -10). Moreover, cPLA2␣-mediated arachidonic acid release is also known to increase COX-2 promoter activity, as well as protein synthesis, thereby redirecting arachidonic ac...