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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.

Pubmed ID: 12351649 RIS Download

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 | Death-Associated Protein Kinases | 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

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Associated grants

  • Agency: NHLBI NIH HHS, Id: R01 HL054118
  • Agency: NHLBI NIH HHS, Id: R01 HL054118-04
  • Agency: NHLBI NIH HHS, Id: R01HL54118

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