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

doi:10.1083/jcb.201010051

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 journal › Article › peer-review

92 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 C ζ (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 language	English (US)
Pages (from-to)	867-84
Number of pages	18
Journal	Journal of Cell Biology
Volume	193
Issue number	5
DOIs	https://doi.org/10.1083/jcb.201010051
State	Published - May 30 2011

Keywords

Animals
Apoptosis
Cells, Cultured
Endothelial Cells
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Protein Kinase C
Regional Blood Flow
SUMO-1 Protein
Sumoylation
Tumor Suppressor Protein p53
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Access to Document

10.1083/jcb.201010051

Cite this

@article{f957eac1cc0b4feab578f07b89b017bb,

title = "PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation",

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 C ζ (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.",

keywords = "Animals, Apoptosis, Cells, Cultured, Endothelial Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Kinase C, Regional Blood Flow, SUMO-1 Protein, Sumoylation, Tumor Suppressor Protein p53, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

author = "Kyung-Sun Heo and Hakjoo Lee and Patrizia Nigro and Tamlyn Thomas and Nhat-Tu Le and Eugene Chang and Carolyn McClain and Reinhart-King, {Cynthia A} and King, {Michael R} and Berk, {Bradford C} and Keigi Fujiwara and Chang-Hoon Woo and Jun-ichi Abe",

year = "2011",

month = may,

day = "30",

doi = "10.1083/jcb.201010051",

language = "English (US)",

volume = "193",

pages = "867--84",

journal = "Journal of Cell Biology",

issn = "0021-9525",

publisher = "Rockefeller University Press",

number = "5",

}

TY - JOUR

T1 - PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation

AU - Heo, Kyung-Sun

AU - Lee, Hakjoo

AU - Nigro, Patrizia

AU - Thomas, Tamlyn

AU - Le, Nhat-Tu

AU - Chang, Eugene

AU - McClain, Carolyn

AU - Reinhart-King, Cynthia A

AU - King, Michael R

AU - Berk, Bradford C

AU - Fujiwara, Keigi

AU - Woo, Chang-Hoon

AU - Abe, Jun-ichi

PY - 2011/5/30

Y1 - 2011/5/30

N2 - 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 C ζ (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.

AB - 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 C ζ (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.

KW - Animals

KW - Apoptosis

KW - Cells, Cultured

KW - Endothelial Cells

KW - Humans

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Protein Kinase C

KW - Regional Blood Flow

KW - SUMO-1 Protein

KW - Sumoylation

KW - Tumor Suppressor Protein p53

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1083/jcb.201010051

DO - 10.1083/jcb.201010051

M3 - Article

C2 - 21624955

SN - 0021-9525

VL - 193

SP - 867

EP - 884

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 5

ER -

PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation

Abstract

Keywords

Access to Document

Fingerprint

Cite this