title: TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis.
abstract: Dysregulated reactive oxygen species (ROS) generation contributes to many human pathologies, including cancer and diabetes. During normal wound repair, inflammation-induced ROS production must be tightly controlled, but the mechanisms reining their generation remain unclear. Herein, we show that transforming growth factor β-activated kinase 1 (TAK1) directly regulates stem cell factor (SCF) expression, which activates the protein kinase B (PKB)α pro-survival pathway in a cell-autonomous manner to protect keratinocytes from ROS-mediated cell death. TAK1 is a pivotal inflammatory mediator whose expression was transiently elevated during wound healing, paralleling the ROS production profile. TAK1 deficiency in keratinocytes led to increased apoptosis in response to anoikis and TNF-α treatment and was associated with elevated ROS level as analyzed by FACS. Using organotypic skin co-culture and comparative growth factor array analysis, we revealed a cell-autonomous mechanism that involved the SCF/c-Kit/PKBα signaling cascade. Ectopic expression of TAK1 or treatment with exogenous recombinant SCF restored the increased ROS production and apoptotic cell death in TAK1-deficient keratinocytes. Conversely, normal keratinocytes treated with various inhibitors targeting the SCF/c-Kit/PKBα pathway exhibited increased ROS production and TNF-α- or anoikis-induced apoptosis. Our study reveals a novel anti-apoptotic role for SCF in keratinocytes and identifies TAK1 as a novel player uniting inflammation and ROS regulation in skin redox biology.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: C R I
authors.initials: CR
authors.lastname: Lam
authors.forename: M J
authors.initials: MJ
authors.lastname: Tan
authors.forename: S H
authors.initials: SH
authors.lastname: Tan
authors.forename: M B Y
authors.initials: MB
authors.lastname: Tang
authors.forename: P C F
authors.initials: PC
authors.lastname: Cheung
authors.forename: N S
authors.initials: NS
authors.lastname: Tan
mesh_terms: D017209:Apoptosis; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7