Nuclear clusterin/XIP8, an x-ray-induced Ku70-binding protein that signals cell death

Chin Rang Yang, Konstantin Leskov, Kelly Hosley-Eberlein, Tracy Criswell, John J. Pink, Timothy J. Kinsella, David A. Boothman

Research output: Contribution to journalArticlepeer-review

236 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5907-5912
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number11
DOIs
StatePublished - May 23 2000

ASJC Scopus subject areas

  • General

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