TBP-associated factor 1 overexpression induces tolerance to Doxorubicin in confluent H9c2 cells by an increase in cdk2 activity and cyclin E expression.
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.
Servant
Nicolas
N
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Québec, Canada.
Marcantonio
Daniela
D
Th'ng
John P H
JP
Chalifour
Lorraine E
LE
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004317:Doxorubicin / Q000633:toxicity*; D004361:Drug Tolerance / Q000235:genetics / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005799:Genes, Dominant / Q000235:genetics; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism; D051548:Histone Acetyltransferases; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000077546:Roscovitine; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics / Q000378:metabolism*; D035362:Transcription Factor TFIID / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; C436291:CDKN1B protein, human; D002352:Carrier Proteins; C493958:Cdkn1a protein, rat; D018797:Cell Cycle Proteins; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011687:Purines; D011994:Recombinant Proteins; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D000077546:Roscovitine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004317:Doxorubicin; D051548:Histone Acetyltransferases; C069001:TATA-binding protein associated factor 250 kDa; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2