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

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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

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Sumoylation
Protein Kinase C
Apoptosis
Endothelial Cells
Atherosclerosis
Proteins
Peroxynitrous Acid
Confocal Microscopy
Blood Vessels
Staining and Labeling
Amino Acids

ASJC Scopus subject areas

  • Cell Biology

Cite this

Heo, K. S., Lee, H., Nigro, P., Thomas, T., Le, N. T., Chang, E., ... 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

PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation. / Heo, Kyung Sun; Lee, Hakjoo; Nigro, Patrizia; Thomas, Tamlyn; Le, Nhat Tu; Chang, Eugene; McClain, Carolyn; Reinhart-King, Cynthia A.; King, Michael R.; Berk, Bradford C.; Fujiwara, Keigi; Woo, Chang Hoon; Abe, Jun Ichi.

In: Journal of Cell Biology, Vol. 193, No. 5, 30.05.2011, p. 867-884.

Research output: Contribution to journalArticle

Heo, KS, Lee, H, Nigro, P, Thomas, T, Le, NT, Chang, E, McClain, C, Reinhart-King, CA, King, MR, Berk, BC, Fujiwara, K, Woo, CH & Abe, JI 2011, 'PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation', Journal of Cell Biology, vol. 193, no. 5, pp. 867-884. https://doi.org/10.1083/jcb.201010051
Heo, Kyung Sun ; Lee, Hakjoo ; Nigro, Patrizia ; Thomas, Tamlyn ; Le, Nhat Tu ; Chang, Eugene ; McClain, Carolyn ; Reinhart-King, Cynthia A. ; King, Michael R. ; Berk, Bradford C. ; Fujiwara, Keigi ; Woo, Chang Hoon ; Abe, Jun Ichi. / PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation. In: Journal of Cell Biology. 2011 ; Vol. 193, No. 5. pp. 867-884.
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AU - Le, Nhat Tu

AU - Chang, Eugene

AU - McClain, Carolyn

AU - Reinhart-King, Cynthia A.

AU - King, Michael R.

AU - Berk, Bradford C.

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AU - Woo, Chang Hoon

AU - Abe, Jun Ichi

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