Abstract
Mixed lineage leukemia (MLL) is a key epigenetic regulator of normal hematopoietic development and chromosomal translocations involving MLL are one of the most common genetic alterations in human leukemia. Here we show that ASB2, a component of the ECS(ASB) E3 ubiquitin ligase complex, mediates MLL degradation through interaction with the PHD/Bromodomain region of MLL. Forced expression of ASB2 degrades MLL and reduces MLL transactivation activity. In contrast, the MLL-AF9 fusion protein does not interact with ASB2 and is resistant to ASB2 mediated degradation. Increased expression of ASB2 during hematopoietic differentiation is associated with decreased levels of MLL protein and down-regulation of MLL target genes. Knockdown of ASB2 leads to increased expression of HOXA9 and delayed cell differentiation. Our data support a model whereby ASB2 contributes to hematopoietic differentiation, in part, through MLL degradation and HOX gene down-regulation. Moreover, deletion of the PHD/Bromo region renders MLL fusion proteins resistant to ASB2-mediated degradation and may contribute to leukemogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation / genetics
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Cells, Cultured
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Cullin Proteins / chemistry
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Cullin Proteins / genetics
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Cullin Proteins / metabolism
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Cullin Proteins / physiology
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Elongin
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HEK293 Cells
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Hematopoiesis* / genetics
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Hematopoiesis* / physiology
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / physiology
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Histone-Lysine N-Methyltransferase
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Humans
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K562 Cells
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Leukemia / etiology
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Leukemia / genetics
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Leukemia / metabolism
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Multiprotein Complexes / physiology
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Myeloid-Lymphoid Leukemia Protein / chemistry
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / metabolism*
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Protein Processing, Post-Translational / genetics
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Protein Processing, Post-Translational / physiology
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Proteolysis*
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SKP Cullin F-Box Protein Ligases / chemistry
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SKP Cullin F-Box Protein Ligases / genetics
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SKP Cullin F-Box Protein Ligases / metabolism
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SKP Cullin F-Box Protein Ligases / physiology*
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Suppressor of Cytokine Signaling Proteins / chemistry
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Suppressor of Cytokine Signaling Proteins / genetics
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Suppressor of Cytokine Signaling Proteins / metabolism
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Suppressor of Cytokine Signaling Proteins / physiology*
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology
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Transfection
Substances
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ASB2 protein, human
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Cullin Proteins
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Elongin
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KMT2A protein, human
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Multiprotein Complexes
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Suppressor of Cytokine Signaling Proteins
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Transcription Factors
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Myeloid-Lymphoid Leukemia Protein
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Histone-Lysine N-Methyltransferase
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SKP Cullin F-Box Protein Ligases