The cdk5 kinase regulates the STAT3 transcription factor to prevent DNA damage upon topoisomerase I inhibition.
The STAT3 transcription factors are cytoplasmic proteins that induce gene activation in response to growth factor stimulation. Following tyrosine phosphorylation, STAT3 proteins dimerize, translocate to the nucleus, and activate specific target genes involved in cell-cycle progression. Despite its importance in cancer cells, the molecular mechanisms by which this protein is regulated in response to DNA damage remain to be characterized. In this study, we show that STAT3 is activated in response to topoisomerase I inhibition. Following treatment, STAT3 is phosphorylated on its C-terminal serine 727 residue but not on its tyrosine 705 site. We also show that topoisomerase I inhibition induced the up-regulation of the cdk5 kinase, a protein initially described in neuronal stress responses. In co-immunoprecipitations, cdk5 was found to associate with STAT3, and pulldown experiments indicated that it associates with the C-terminal activation domain of STAT3 upon DNA damage. Importantly, the cdk5-STAT3 pathway reduced DNA damage in response to topoisomerase I inhibition through the up-regulation of Eme1, an endonuclease involved in DNA repair. ChIP experiments indicated that STAT3 can be found associated with the Eme1 promoter when phosphorylated only on its serine 727 residue and not on tyrosine 705. We therefore propose that the cdk5-STAT3 oncogenic pathway plays an important role in the expression of DNA repair genes and that these proteins could be used as predictive markers of tumors that will fail to respond to chemotherapy.
Paul Papin Cancer Center, INSERM U892, 2 rue Moll, 49933 Angers, France.
Sandy
S
Courapied
Paul Papin Cancer Center, INSERM U892, 2 rue Moll, 49933 Angers, France.
Hélène
H
Sellier
Paul Papin Cancer Center, INSERM U892, 2 rue Moll, 49933 Angers, France.
Sophie
S
de Carné Trécesson
Paul Papin Cancer Center, INSERM U892, 2 rue Moll, 49933 Angers, France.
Arnaud
A
Vigneron
Paul Papin Cancer Center, INSERM U892, 2 rue Moll, 49933 Angers, France.
Anne-Charlotte
AC
Bernard
Paul Papin Cancer Center, INSERM U892, 2 rue Moll, 49933 Angers, France.
Erick
E
Gamelin
Paul Papin Cancer Center, INSERM U892, 2 rue Moll, 49933 Angers, France.
Benjamin
B
Barré
Paul Papin Cancer Center, INSERM U892, 2 rue Moll, 49933 Angers, France. Electronic address: olivier.coqueret@univ-angers.fr.
Olivier
O
Coqueret
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D055503:Protein Multimerization / Q000187:drug effects / Q000235:genetics; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors
D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D059004:Topoisomerase I Inhibitors; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C507947:Eme1 protein, human; D004706:Endodeoxyribonucleases; D004264:DNA Topoisomerases, Type I