Abstract
A genome wide search for new BH3-containing Bcl-2 family members was conducted using position weight matrices (PWM) and identified a large (480kDa), novel BH3-only protein, originally called LASU1 (now also known as Ureb-1, E3(histone), ARF-BP1, and Mule). We demonstrated that LASU1 is an E3 ligase that ubiquitinated Mcl-1 in vitro and was required for its proteasome-dependent degradation in HeLa cells. Of note, the BH3 domain of LASU1 interacted with Mcl-1 but not with Bcl-2 or Bcl-Xl. A competing BH3-ligand derived from Bim interacted with Mcl-1 and prevented its interaction with LASU1 in HeLa cells, causing elevation of the steady-state levels of Mcl-1. This suggests that the unliganded form of Mcl-1 is sensitive to LASU1-mediated degradation of Mcl-1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Cells, Cultured
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Computational Biology
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Humans
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Ligands
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Molecular Sequence Data
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / metabolism*
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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Tumor Suppressor Proteins
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Ubiquitin-Protein Ligases / chemistry*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitins / metabolism
Substances
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Ligands
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Tumor Suppressor Proteins
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Ubiquitins
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HUWE1 protein, human
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Ubiquitin-Protein Ligases