title: The PP2A inhibitor SET regulates granzyme B expression in human natural killer cells.
abstract: The ability of natural killer (NK) cells to kill malignant or infected cells depends on the integration of signals from different families of cell surface receptors, including cytokine receptors. How such signals then regulate NK-cell cytotoxicity is incompletely understood. Here we analyzed an endogenous inhibitor of protein phosphatase 2A (PP2A) activity called SET, and its role in regulating human NK-cell cytotoxicity and its mechanism of action in human NK cells. RNAi-mediated suppression of SET down-modulates NK-cell cytotoxicity, whereas ectopic overexpression of SET enhances cytotoxicity. SET knockdown inhibits both mRNA and protein granzyme B expression, as well as perforin expression, whereas SET overexpression enhances granzyme B expression. Treatment of NK cells with the PP2A activator 1,9-dideoxy-forskolin also inhibits both granzyme B expression and cytotoxicity. In addition, pretreatment with the PP2A inhibitor okadaic acid rescues declining granzyme B mRNA levels in SET knockdown cells. Down-modulation of SET expression or activation of PP2A also decreases human NK-cell antibody-dependent cellular cytotoxicity. Finally, the induction of granzyme B gene expression by interleukin-2 and interleukin-15 is inhibited by SET knockdown. These data provide evidence that granzyme B gene expression and therefore human NK-cell cytotoxicity can be regulated by the PP2A-SET interplay.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, 460 West 12th Ave., Columbus, OH 43210, USA. rossana.trotta@osumc.edu
authors.forename: Rossana
authors.initials: R
authors.lastname: Trotta
authors.forename: David
authors.initials: D
authors.lastname: Ciarlariello
authors.forename: Jessica
authors.initials: J
authors.lastname: Dal Col
authors.forename: Hsiaoyin
authors.initials: H
authors.lastname: Mao
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Edward
authors.initials: E
authors.lastname: Briercheck
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053804:Granzymes / Q000096:biosynthesis / Q000235:genetics*; D056488:Histone Chaperones / Q000502:physiology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056488:Histone Chaperones; D034741:RNA, Small Interfering; C513473:SET protein, human; D014157:Transcription Factors; D054648:Protein Phosphatase 2; D053804:Granzymes