Protein Kinase Cδ Regulates Apoptosis via Activation of STAT1

• Published in: The Journal of biological chemistry Vol. 279; no. 44; p. 45603
• Main Authors: Tracie A. DeVries, Rachelle L. Kalkofen, Angela A. Matassa, Mary E. Reyland
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 29.10.2004
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M407448200

Protein kinase Cδ (PKCδ) is required for mitochondria-dependent apoptosis; however, little is known about downstream effectors of PKCδ in apoptotic cells. Here we show that activation of STAT1 is an early response to DNA damage and that STAT1 activation requires PKCδ. Treatment of HeLa cells with etoposide results in phosphorylation of STAT1 on Ser 727 and the association of STAT1 with PKCδ. 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 PKCδ. To ask if STAT1 is required for PKCδ-mediated apoptosis, we utilized U3A STAT1-deficient cells. Induction of apoptosis by PKCδ is suppressed in U3A cells but can be rescued by co-transfection with STAT1α but not STAT1 mutated at Ser 727 . Nuclear accumulation of STAT1, phospho-Ser 727 STAT1, and PKCδ are detectable 30–60 min after treatment with etoposide. Nuclear localization is necessary for apoptosis, since a nuclear localization mutant of PKCδ does not induce apoptosis in U3A cells reconstituted with STAT1α, and a nuclear localization mutant of STAT1 does not support PKCδ-induced apoptosis in U3A cells. Our data identify STAT1 as a downstream target of PKCδ and suggest that PKCδ may regulate apoptosis by activation of STAT1 target genes.