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The Burnham Institute, La Jolla, California 92037 [S. T., S. Kr., M. K., S. Ki., J. M. Z., K. K., D. K., J. C. R.]; Science Applications International Corporation Frederick, National Cancer Institute-Frederick Cancer Research & Development Center, Frederick, Maryland 21702 [D. S., G. T.]; University of Colorado Health Science Center, Department of Pathology, Denver, Colorado 80262 [G. J. M.]; and The National Children's Medical Research Center, Department of Genetics, Tokyo 154, Japan [T. M., M. Y.]
BAG-1 is a multifunctional protein that blocks apoptosis and interacts with several types of proteins, including Bcl-2 family proteins, the kinase Raf-1, certain tyrosine kinase growth factor receptors, and steroid hormone receptors, possibly by virtue of its ability to regulate the Hsp70/Hsc70 family of molecular chaperones. Two major forms of the human and mouse BAG-1 proteins were detected by immunoblotting. The longer human and mouse BAG-1 proteins (BAG-1L) appear to arise through translation initiation at noncanonical CTG codons located upstream of and in-frame with the usual ATG codon used for production of the originally described BAG-1 protein. Immunoblotting experiments using normal tissues revealed that BAG-1L is far more restricted in its expression and is present at lower levels than the more prevalent BAG-1 protein. Human but not mouse tissues also produce small amounts of an additional isoform of BAG-1 of intermediate size (BAG-1M) that probably arises through translation initiation at yet another site involving an ATG codon. All three isoforms of human BAG-1 (BAG-1, BAG-1M, and BAG-1L) retained the ability to bind Hsc70. Subcellular fractionation and immunofluorescence confocal microscopy studies indicated that BAG-1L often resides in the nucleus, consistent with the presence of a nuclear localization sequence in the NH2-terminal unique domain of this protein. In immunohistochemical assays, BAG-1 immunoreactivity was detected in a wide variety of types of cells in normal adult tissues and was localized to either cytosol, nucleus, or both, depending on the particular type of cell. In some cases, cytosolic BAG-1 immunostaining was clearly associated with organelles resembling mitochondria, consistent with the reported interaction of BAG-1 with Bcl-2 and related proteins. Furthermore, experiments using a green fluorescence protein (GFP)-BAG-1 fusion protein demonstrated that overexpression of Bcl-2 in cultured cells can cause intracellular redistribution of GFP-BAG-1, producing a membranous pattern typical of Bcl-2 family proteins. The BAG-1 protein was found at high levels in several types of human tumor cell lines among the 67 tested, particularly leukemias, breast, prostate, and colon cancers. In contrast to normal tissues, which only rarely expressed BAG-1L, tumor cell lines commonly contained BAG-1L protein, including most prostate, breast, and leukemia cell lines, suggesting that a change in BAG-1 mRNA translation frequently accompanies malignant transformation.
1 This work was supported by Grant CA67329 from the NIH/National Cancer Institute. J. M. Z. was a recipient of a fellowship from the Fulbright/Spaniard Ministry of Education and Science and is presently supported by funds provided by the Breast Cancer Fund of the State of California through the Breast Cancer Research Program of the University of California (#3FB-0093). D. K. is a recipient of a fellowship from the Susan B. Komen Foundation, as well as a Wellcome Travel Grant.
2 To whom requests for reprints should be addressed, at The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. Phone: (619) 646-3140; Fax: (619) 646-3194; E-mail: jreed@burnham-inst.org.
Received 8/ 7/97. Accepted 5/18/98.
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