title: hSMG-1 is a granzyme B-associated stress-responsive protein kinase.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U753; Laboratoire d'immunologie des tumeurs humaines: interaction effecteurs cytotoxiques-système tumoral, Institut Gustave Roussy PR1 and IFR 54, 94805 Villejuif Cedex, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Meslin
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hamaï
authors.forename: Bernhard
authors.initials: B
authors.lastname: Mlecnik
authors.forename: Filippo
authors.initials: F
authors.lastname: Rosselli
authors.forename: Catherine
authors.initials: C
authors.lastname: Richon
authors.forename: Abdelali
authors.initials: A
authors.lastname: Jalil
authors.forename: Gregory
authors.initials: G
authors.lastname: Wemhoff
authors.forename: Jerome
authors.initials: J
authors.lastname: Thiery
authors.forename: Jerome
authors.initials: J
authors.lastname: Galon
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
mesh_terms: D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D004249:DNA Damage / Q000187:drug effects; D003851:Deoxyribonucleases / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D053804:Granzymes / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D013312:Stress, Physiological / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
chemical_list: D003851:Deoxyribonucleases; D053804:Granzymes; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; C514704:SMG1 protein, human; C109663:caspase-activated deoxyribonuclease