A death-associated protein kinase (DAPK)-interacting protein, DIP-1, is an E3 ubiquitin ligase that promotes tumor necrosis factor-induced apoptosis and regulates the cellular levels of DAPK.
Death-associated protein kinase (DAPK) is a multi-domain Ser/Thr protein kinase with an important role in apoptosis regulation. In these studies we have identified a DAPK-interacting protein called DIP-1, which is a novel multi-RING finger protein. The RING finger motifs of DIP-1 have E3 ligase activity that can auto-ubiquitinate DIP-1 in ... vitro. In vivo, DIP-1 is detected as a polyubiquitinated protein, suggesting that the intracellular levels of DIP-1 are regulated by the ubiquitin-proteasome system. Transient expression of DIP-1 in HeLa cells antagonizes the anti-apoptotic function of DAPK to promote a caspase-dependent apoptosis. These studies also demonstrate that DAPK is an in vitro and in vivo target for ubiquitination by DIP-1, thereby providing a mechanism by which DAPK activities can be regulated through proteasomal degradation.
Mesh Terms:
Amino Acid Sequence, Animals, Apoptosis, Apoptosis Regulatory Proteins, Blotting, Northern, Blotting, Western, COS Cells, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cloning, Molecular, Cysteine Endopeptidases, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Flow Cytometry, Fungal Proteins, Gene Expression Regulation, Enzymologic, Hela Cells, Humans, Ligases, Mice, Molecular Sequence Data, Multienzyme Complexes, Precipitin Tests, Proteasome Endopeptidase Complex, Protein Binding, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Substrate Specificity, Time Factors, Tissue Distribution, Tumor Necrosis Factor-alpha, Two-Hybrid System Techniques, Ubiquitin, Ubiquitin-Protein Ligases
Amino Acid Sequence, Animals, Apoptosis, Apoptosis Regulatory Proteins, Blotting, Northern, Blotting, Western, COS Cells, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cloning, Molecular, Cysteine Endopeptidases, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Flow Cytometry, Fungal Proteins, Gene Expression Regulation, Enzymologic, Hela Cells, Humans, Ligases, Mice, Molecular Sequence Data, Multienzyme Complexes, Precipitin Tests, Proteasome Endopeptidase Complex, Protein Binding, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Substrate Specificity, Time Factors, Tissue Distribution, Tumor Necrosis Factor-alpha, Two-Hybrid System Techniques, Ubiquitin, Ubiquitin-Protein Ligases
J. Biol. Chem.
Date: Dec. 06, 2002
PubMed ID: 12351649
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