TY - JOUR
T1 - Nuclear clusterin/XIP8, an x-ray-induced Ku70-binding protein that signals cell death
AU - Yang, Chin Rang
AU - Leskov, Konstantin
AU - Hosley-Eberlein, Kelly
AU - Criswell, Tracy
AU - Pink, John J.
AU - Kinsella, Timothy J.
AU - Boothman, David A.
PY - 2000/5/23
Y1 - 2000/5/23
N2 - Clusterin [CLU, a.k.a. TRPM-2, SGP-2, or ionizing radiation (IR)-induced protein-8 (XIP8)] was implicated in apoptosis, tissue injury, and aging. Its function remains elusive. We reisolated CLU/XIP8 by yeast two-hybrid analyses using as bait the DNA double-strand break repair protein Ku70. We show that a delayed (2-3 days), low-dose (0.02-10 Gy) IR-inducible nuclear CLU/XIP8 protein coimmunoprecipitated and colocalized (by confocal microscopy) in vivo with Ku70/Ku80, a DNA damage sensor and key double-strand break repair protein, in human MCF-7:WS8 breast cancer cells. Overexpression of nuclear CLU/XIP8 or its minimal Ku70 binding domain (120 aa of CLU/XIP8 C terminus) in nonirradiated MCF-7:WS8 cells dramatically reduced cell growth and colony- forming ability concomitant with increased G1 cell cycle checkpoint arrest and increased cell death. Enhanced expression and accumulation of nuclear CLU/XIP8-Ku70/Ku80 complexes appears to be an important cell death signal after IR exposure.
AB - Clusterin [CLU, a.k.a. TRPM-2, SGP-2, or ionizing radiation (IR)-induced protein-8 (XIP8)] was implicated in apoptosis, tissue injury, and aging. Its function remains elusive. We reisolated CLU/XIP8 by yeast two-hybrid analyses using as bait the DNA double-strand break repair protein Ku70. We show that a delayed (2-3 days), low-dose (0.02-10 Gy) IR-inducible nuclear CLU/XIP8 protein coimmunoprecipitated and colocalized (by confocal microscopy) in vivo with Ku70/Ku80, a DNA damage sensor and key double-strand break repair protein, in human MCF-7:WS8 breast cancer cells. Overexpression of nuclear CLU/XIP8 or its minimal Ku70 binding domain (120 aa of CLU/XIP8 C terminus) in nonirradiated MCF-7:WS8 cells dramatically reduced cell growth and colony- forming ability concomitant with increased G1 cell cycle checkpoint arrest and increased cell death. Enhanced expression and accumulation of nuclear CLU/XIP8-Ku70/Ku80 complexes appears to be an important cell death signal after IR exposure.
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U2 - 10.1073/pnas.97.11.5907
DO - 10.1073/pnas.97.11.5907
M3 - Article
C2 - 10823943
AN - SCOPUS:0034705103
SN - 0027-8424
VL - 97
SP - 5907
EP - 5912
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -