Distinct role of Kruppel-like factor 11 in the regulation of prostaglandin E2 biosynthesis.
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.
Buttar
Navtej S
NS
Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota 55902, USA. buttar.navtej@mayo.edu
DeMars
Cathrine J
CJ
Lomberk
Gwen
G
Ilyas
Sumera I
SI
Bonilla-Velez
Juliana
J
Achra
Shalini
S
Rashtak
Shahrooz
S
Wang
Kenneth K
KK
Fernandez-Zapico
Martin E
ME
Urrutia
Raul
R
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D016466:CHO Cells; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D002843:Chromatin / Q000737:chemistry; D006224:Cricetinae; D003412:Cricetulus; D015232:Dinoprostone / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008954:Models, Biological; D008957:Models, Genetic; D054467:Phospholipases A2 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D016335:Zinc Fingers
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; C115117:KLF11 protein, human; D008055:Lipids; D012097:Repressor Proteins; D054467:Phospholipases A2; D015232:Dinoprostone