hSMG-1 is a granzyme B-associated stress-responsive protein kinase

J Mol Med (Berl). 2011 Apr;89(4):411-21. doi: 10.1007/s00109-010-0708-0. Epub 2011 Feb 8.

Abstract

Granzyme B plays a key role in cell-mediated programmed cell death. We previously demonstrated that p53 is a functional determinant in the granzyme B-induced cytotoxic T-lymphocyte response. However, the pathways leading to activation of p53 by granzyme B remain incompletely understood. We now demonstrate that granzyme B-induced DNA damage signaling as revealed by histone H2AX phosphorylation and subsequent activation of the stress kinase CHK2. Confocal microscopy analysis indicates that granzyme B treatment of tumor cells induced an early translocation of endonuclease caspase-activated DNase. DNA microarray-based global transcriptional profiling and RT-PCR indeed revealed genes related to DNA damage. Among these genes, hSMG-1, a genotoxic stress-activated protein, was constantly upregulated in tumor cells following granzyme B treatment. Knockdown of the hSMG-1 gene in T1 tumor target cell line resulted in a significant inhibition of granzyme B- and CTL-induced killing. Our data suggest that granzyme B may exert cell death through DNA damage signaling and uncover a novel molecular link between the DNA damage pathway and granzyme B-induced cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Nucleus / enzymology
  • DNA Damage / drug effects
  • Deoxyribonucleases / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Granzymes / metabolism
  • Granzymes / pharmacology*
  • Humans
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Transport / drug effects
  • Protein-Serine-Threonine Kinases
  • RNA Interference
  • Stress, Physiological / drug effects
  • T-Lymphocytes, Cytotoxic / drug effects*
  • T-Lymphocytes, Cytotoxic / immunology

Substances

  • Protein-Serine-Threonine Kinases
  • SMG1 protein, human
  • Deoxyribonucleases
  • caspase-activated deoxyribonuclease
  • Granzymes