Abstract
Doxorubicin (DOX) is a DNA topoisomerase II inhibitor widely used in anticancer treatment, however, it can lead to irreversible cardiac damage with severe debilitation. TBP-binding associated factor 1 (TAF1) is increased in DOX damaged hearts in vivo and in cardiomyocytes in vitro. To identify the functional role for TAF1 in DOX-treated heart we overexpressed wild type and mutant TAF1 in H9c2 cells. Overexpression of wild-type TAF1, but not N-terminal kinase domain mutants, increased tolerance to DOX in confluent cells. DOX treatment can cause prolonged G1 arrest. We found increased cdk2 activity coupled to increased cyclin E protein and decreased p21(waf1Cip1) and p27(Kip1) protein to correlate only with increased DOX tolerance and wild-type TAF1. DOX sensitivity was restored when the cdk2-inhibitor Roscovitine was co-administered with DOX. Overexpression of cdk2-alone increased resistance to DOX. Thus, TAF1 induced DOX tolerance in confluent cells through an increase in cdk2 activity is directed by the TAF1 N-terminal domain. These studies suggest new avenues for myocardial protection against DOX toxicity and suggest a role for cdk2 in chemorefractory cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibiotics, Antineoplastic / toxicity*
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CDC2-CDC28 Kinases / antagonists & inhibitors
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CDC2-CDC28 Kinases / metabolism*
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Carrier Proteins / metabolism
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Cell Cycle Proteins / metabolism
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Cell Line
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Cyclin E / metabolism*
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Doxorubicin / toxicity*
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Drug Tolerance / genetics
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Drug Tolerance / physiology*
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Gene Expression Regulation / physiology
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Genes, Dominant / genetics
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Heart Diseases / chemically induced
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Heart Diseases / metabolism
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Histone Acetyltransferases
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Intracellular Signaling Peptides and Proteins / metabolism
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Mutation / genetics
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Myocytes, Cardiac / metabolism
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Protein Structure, Tertiary / genetics
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Protein Structure, Tertiary / physiology
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Purines / pharmacology
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Rats
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Roscovitine
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Signal Transduction / drug effects
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Signal Transduction / genetics
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TATA-Binding Protein Associated Factors / genetics
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TATA-Binding Protein Associated Factors / metabolism*
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Transcription Factor TFIID / genetics
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Transcription Factor TFIID / metabolism*
Substances
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Antibiotics, Antineoplastic
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CDKN1B protein, human
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Carrier Proteins
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Cdkn1a protein, rat
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Cell Cycle Proteins
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Cyclin E
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Cyclin-Dependent Kinase Inhibitor p21
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Purines
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Recombinant Proteins
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TATA-Binding Protein Associated Factors
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Transcription Factor TFIID
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Roscovitine
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Cyclin-Dependent Kinase Inhibitor p27
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Doxorubicin
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Histone Acetyltransferases
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TATA-binding protein associated factor 250 kDa
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CDC2-CDC28 Kinases
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Cdk2 protein, rat
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Cyclin-Dependent Kinase 2