Protein kinase C delta induces apoptosis of vascular smooth muscle cells through induction of the tumor suppressor p53 by both p38-dependent and p38-independent mechanisms.
Apoptotic death of vascular smooth muscle cells (SMCs) is a prominent feature of blood vessel remodeling. In the present study, we examined the novel PKC isoform protein kinase C delta (PKCdelta) and its role in vascular SMC apoptosis. In A10 SMCs, overexpression of PKCdelta was sufficient to induce apoptosis, whereas inhibition of PKCdelta diminished H2O2-induced apoptosis. Moreover, evidence is provided that the tumor suppressor p53 is an essential mediator of PKCdelta-induced apoptosis in SMCs. Activation of PKCdelta led to accumulation as well as phosphorylation of p53 in SMCs; this induction correlated with apoptosis. Furthermore, blocking p53 induction with small interference RNA or targeted gene deletion prevented PKCdelta-induced apoptosis, whereas restoring p53 expression rescued the ability of PKCdelta to induce apoptosis in p53 null SMCs. We also establish that PKCdelta regulates p53 at both transcriptional and post-translational levels. Specifically, the transcriptional regulation required p38 MAPK, whereas the post-translational modification, at least for serine 46, did not involve MAPK. Additionally, PKCdelta, p38 MAPK, and p53 co-associate in cells under conditions favoring apoptosis. Together, our data suggest that SMC apoptosis proceeds through a pathway that involves PKCdelta, the intermediary p38 MAPK, and the downstream target tumor suppressor p53.
Ryer
Evan J
EJ
Department of Surgery, Division of Vascular Surgery, New York Presbyterian Hospital and Weill Medical College, Cornell University, New York, New York 10021, USA.
Sakakibara
Kenji
K
Wang
Chunjie
C
Sarkar
Devanand
D
Fisher
Paul B
PB
Faries
Peter L
PL
Kent
K Craig
KC
Liu
Bo
B
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D017209:Apoptosis; D002478:Cells, Cultured; D017353:Gene Deletion; D005822:Genetic Vectors; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015151:Immunoblotting; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000166:cytology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D010766:Phosphorylation; D020033:Protein Isoforms; D051745:Protein Kinase C-delta / Q000378:metabolism / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; D008156:Luciferases; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases