PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation

Kyung Sun Heo, Hakjoo Lee, Patrizia Nigro, Tamlyn Thomas, Nhat Tu Le, Eugene Chang, Carolyn McClain, Cynthia A. Reinhart-King, Michael R. King, Bradford C. Berk, Keigi Fujiwara, Chang Hoon Woo, Jun Ichi Abe

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Atherosclerosis is readily observed in regions of blood vessels where disturbed blood flow (d-flow) is known to occur. A positive correlation between protein kinase Cζ (PKCζ) activation and d-flow has been reported, but the exact role of d-flow-mediated PKCζ activation in atherosclerosis remains unclear. We tested the hypothesis that PKCζ activation by d-flow induces endothelial cell (EC) apoptosis by regulating p53. We found that d-flow-mediated peroxynitrite (ONOO-) increased PKCζ activation, which subsequently induced p53 SUMOylation, p53-Bcl-2 binding, and EC apoptosis. Both d-flow and ONOO- increased the association of PKCζ with protein inhibitor of activated STATy (PIASy) via the Siz/PIAS-RING domain (amino acids 301-410) of PIASy, and overexpression of this domain of PIASy disrupted the PKCζ-PIASy interaction and PKCζ-mediated p53 SUMOylation. En face confocal microscopy revealed increases in nonnuclear p53 expression, nitrotyrosine staining, and apoptosis in aortic EC located in d-flow areas in wild-type mice, but these effects were significantly decreased in p53-/- mice. We propose a novel mechanism for p53 SUMOylation mediated by the PKCζ-PIASy interaction during d-flow-mediated EC apoptosis, which has potential relevance to early events of atherosclerosis.

Original languageEnglish (US)
Pages (from-to)867-884
Number of pages18
JournalJournal of Cell Biology
Volume193
Issue number5
DOIs
StatePublished - May 30 2011

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation'. Together they form a unique fingerprint.

  • Cite this

    Heo, K. S., Lee, H., Nigro, P., Thomas, T., Le, N. T., Chang, E., McClain, C., Reinhart-King, C. A., King, M. R., Berk, B. C., Fujiwara, K., Woo, C. H., & Abe, J. I. (2011). PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation. Journal of Cell Biology, 193(5), 867-884. https://doi.org/10.1083/jcb.201010051