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Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis.

Cell | Jul 1, 2005

The elimination of Mcl-1, an anti-apoptotic Bcl-2 family member, is an early and required step for DNA damage-induced apoptosis. The degradation of Mcl-1 can be blocked by proteasome inhibitors, suggesting a role for the ubiquitin proteasome pathway in apoptosis. Here, we demonstrate that Mcl-1 is ubiquinated at five lysines. Biochemical fractionation of cell extracts allowed us to identify a 482 kDa HECT-domain-containing ubiquitin ligase named Mule (Mcl-1 ubiquitin ligase E3) that is both required and sufficient for the polyubiquitination of Mcl-1. Mule also contains a region similar to the Bcl-2 homology region 3 (BH3) domain that allows Mule to specifically interact with Mcl-1. Elimination of Mule expression by RNA interference stabilizes Mcl-1 protein, resulting in an attenuation of the apoptosis induced by DNA-damage agents. Thus, Mule is a unique BH3-containing E3 ubiquitin ligase apical to Bcl-2 family proteins during DNA damage-induced apoptosis.

Pubmed ID: 15989957 RIS Download

Mesh terms: Amino Acid Sequence | Animals | Apoptosis | Catalytic Domain | DNA Damage | Humans | Molecular Sequence Data | Myeloid Cell Leukemia Sequence 1 Protein | Neoplasm Proteins | Proto-Oncogene Proteins c-bcl-2 | RNA Interference | RNA Stability | Ubiquitin | Ubiquitin-Protein Ligases

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Associated grants

  • Agency: NIGMS NIH HHS, Id: GMR01-57158

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