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J. Biol. Chem., Vol. 278, Issue 13, 11590-11600, March 28, 2003
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From the Department of Radiation Oncology, Laboratory of Molecular
Stress Responses, Ireland Comprehensive Cancer Center and Case
Western Reserve University School of Medicine,
Cleveland, Ohio 44106-4942
Nuclear clusterin (nCLU) is an ionizing radiation
(IR)-inducible protein that binds Ku70, and triggers apoptosis when
overexpressed in MCF-7 cells. We demonstrate that endogenous nCLU
synthesis is a product of alternative splicing. Reverse
transcriptase-PCR analyses revealed that exon II, containing the first
AUG and encoding the endoplasmic reticulum-targeting peptide, was
omitted. Exons I and III are spliced together placing a downstream AUG
in exon III as the first available translation start site. This shorter mRNA produces the 49-kDa precursor nCLU protein. Ku70 binding activity was localized to the C-terminal coiled-coil domain of nCLU.
Leucine residues 357, 358, and 361 of nCLU were necessary for Ku70-nCLU
interaction. The N- and C-terminal coiled-coil domains of nCLU
interacted with each other, suggesting that the protein could dimerize
or fold. Mutation analyses indicate that the C-terminal NLS was
functional in nCLU with the same contribution from N-terminal NLS. The
C-terminal coiled-coil domain of nCLU was the minimal region required
for Ku binding and apoptosis. MCF-7 cells show nuclear as well as
cytoplasmic expression of GFP-nCLU in apoptotic cells. Cytosolic
aggregation of GFP-nCLU was found in viable cells. These results
indicate that an inactive precursor of nCLU exists in the cytoplasm of
non-irradiated MCF-7 cells, translocates into the nucleus following IR,
and induces apoptosis.
Synthesis and Functional Analyses of Nuclear Clusterin, a Cell
Death Protein*
*
This work was supported by NCI Grants CA78530 (to
D. A. B.) and CA84578 (to T. J. K.) from the National Institutes of
Health and by the Department of Defense Breast Cancer Research Program DAMD17-01-1-0196 (to K. S. L.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Radiation
Oncology (BRB-326 East), Laboratory of Molecular Stress Responses, Case
Western Reserve University, 10900 Euclid Ave., Cleveland, OH
44106-4942. Tel.: 216-368-0840; Fax: 216-368-1142; E-mail: dab30@po.cwru.edu.
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