Abstract
Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation. We also show that the Ser291-phosphorylated form of the multifunctional protein and stem cell marker, CD44, inhibits FBXO21-directed degradation of P-gp. Thus, CD44 increases P-gp mediated drug resistance and represents a potential therapeutic target in P-gp-positive cells.
Keywords:
drug resistance; ubquitination.
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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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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Animals
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BALB 3T3 Cells
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Drug Resistance, Multiple* / genetics
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Drug Resistance, Neoplasm* / genetics
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F-Box Proteins / genetics
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F-Box Proteins / metabolism*
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Female
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism*
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MCF-7 Cells
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Mice
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Phosphorylation
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding
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Protein Stability
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Proteolysis
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RNA Interference
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Serine
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Time Factors
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Transfection
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Two-Hybrid System Techniques
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Ubiquitination*
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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CD44 protein, human
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F-Box Proteins
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FBXO21 protein, human
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Hyaluronan Receptors
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Serine
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Proteasome Endopeptidase Complex