CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance

Cell Rep. 2013 Aug 15;4(3):437-44. doi: 10.1016/j.celrep.2013.07.012. Epub 2013 Aug 8.

Abstract

The transcription factor STAT1 is important in natural killer (NK) cells, which provide immediate defense against tumor and virally infected cells. We show that mutation of a single phosphorylation site (Stat1-S727A) enhances NK cell cytotoxicity against a range of tumor cells, accompanied by increased expression of perforin and granzyme B. Stat1-S727A mice display significantly delayed disease onset in NK cell-surveilled tumor models including melanoma, leukemia, and metastasizing breast cancer. Constitutive phosphorylation of S727 depends on cyclin-dependent kinase 8 (CDK8). Inhibition of CDK8-mediated STAT1-S727 phosphorylation may thus represent a therapeutic strategy for stimulating NK cell-mediated tumor surveillance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 8 / metabolism*
  • Cytotoxicity, Immunologic
  • Female
  • Immunologic Surveillance
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Leukemia, Experimental / immunology*
  • Leukemia, Experimental / metabolism
  • Leukemia, Experimental / pathology
  • Mammary Neoplasms, Experimental / immunology*
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Phosphorylation
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction

Substances

  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Cdk8 protein, mouse
  • Cyclin-Dependent Kinase 8