Protein kinase Cdelta regulates apoptosis via activation of STAT1.
Protein kinase Cdelta (PKCdelta) is required for mitochondria-dependent apoptosis; however, little is known about downstream effectors of PKCdelta in apoptotic cells. Here we show that activation of STAT1 is an early response to DNA damage and that STAT1 activation requires PKCdelta. Treatment of HeLa cells with etoposide results in phosphorylation of STAT1 on Ser(727) and the association of STAT1 with PKCdelta. Etoposide increases transcription from STAT1-dependent reporter constructs. Increased transcription, as well as STAT1 Ser(727) phosphorylation, can be blocked by inhibition or depletion of PKCdelta. To ask if STAT1 is required for PKCdelta-mediated apoptosis, we utilized U3A STAT1-deficient cells. Induction of apoptosis by PKCdelta is suppressed in U3A cells but can be rescued by co-transfection with STAT1alpha but not STAT1 mutated at Ser(727). Nuclear accumulation of STAT1, phospho-Ser(727) STAT1, and PKCdelta are detectable 30-60 min after treatment with etoposide. Nuclear localization is necessary for apoptosis, since a nuclear localization mutant of PKCdelta does not induce apoptosis in U3A cells reconstituted with STAT1alpha, and a nuclear localization mutant of STAT1 does not support PKCdelta-induced apoptosis in U3A cells. Our data identify STAT1 as a downstream target of PKCdelta and suggest that PKCdelta may regulate apoptosis by activation of STAT1 target genes.
DeVries
Tracie A
TA
Department of Craniofacial Biology, School of Dentistry, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Kalkofen
Rachelle L
RL
Matassa
Angela A
AA
Reyland
Mary E
ME
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D051745:Protein Kinase C-delta; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D005047:Etoposide; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta