Isolation of Bcl-2 binding proteins that exhibit homology with BAG-1 and suppressor of death domains protein.
The Bcl-2 oncoprotein is a potent inhibitor of apoptosis and is overexpressed in a variety of different malignancies. Bcl-2 function is regulated through heterodimerization with other members of the Bcl-2 protein family. In addition, several proteins that are not members of the Bcl-2 family can bind to Bcl-2, including BAG-1 ... protein. In this study, we screened for proteins that bind to Bcl-2, and isolated two additional members of the BAG-1 protein family, BAG-3 and BAG-4. The BAG-4 protein that we cloned also corresponds to the recently isolated suppressor of death domains (SODD) protein, a molecule that binds and inhibits signaling by tumor necrosis factor receptor 1 (TNFR1). Both BAG-3 and BAG-4/SODD were found to physically associate with Bcl-2, and both proteins are well conserved from human to mouse. A region of homology, comprising 68 amino acids, is present in the carboxyl termini of BAG-3 and BAG-4/SODD, and this region corresponds with sequences termed BAG domains that are found in other members of the BAG-1 protein family. In BAG-3 and BAG-4/SODD, the BAG domains appear to constitute the Bcl-2 binding regions of these molecules. BAG-3 and BAG-4/SODD, like BAG-1, were also shown to bind to Hsp70 inside the cell. Moreover, BAG-3 overexpression modestly inhibited apoptosis resulting from cytokine deprivation of IL-3-dependent 32D cells. Together, our findings demonstrate that other members of the BAG-1 protein family, namely BAG-3 and BAG-4/SODD, bind to Bcl-2 and provide a potential link between pathways regulated by Bcl-2 and pathways regulated by Hsp70, as well as TNFR1.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Antigens, CD, Baculoviridae, Carrier Proteins, Cell Line, Cloning, Molecular, Conserved Sequence, DNA, Complementary, DNA-Binding Proteins, Gene Library, HSP70 Heat-Shock Proteins, Humans, Insects, Interleukin-3, Mice, Molecular Sequence Data, Multigene Family, Precipitin Tests, Protein Binding, Protein Biosynthesis, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Signal Transduction, Transcription Factors, Transfection
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Antigens, CD, Baculoviridae, Carrier Proteins, Cell Line, Cloning, Molecular, Conserved Sequence, DNA, Complementary, DNA-Binding Proteins, Gene Library, HSP70 Heat-Shock Proteins, Humans, Insects, Interleukin-3, Mice, Molecular Sequence Data, Multigene Family, Precipitin Tests, Protein Binding, Protein Biosynthesis, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Signal Transduction, Transcription Factors, Transfection
Biochem. Biophys. Res. Commun.
Date: Sep. 07, 2001
PubMed ID: 11527400
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