title: Mechanism of anthracycline-mediated down-regulation of GATA4 in the heart.
abstract: OBJECTIVE
  Anthracyclines such as daunorubicin (DNR) and doxorubicin are effective cancer chemotherapeutic agents, but can induce cardiotoxicity. GATA4 has been shown to serve as a survival factor of cardiac muscle cells, and anthracyclines promote apoptosis in part by down-regulating GATA4. The present study investigated the mechanism of anthracycline action to down-regulate GATA4.
  
  
  RESULTS
  DNR inhibited the transcriptional activity exhibited by the 250 bp conserved region immediately upstream from the transcriptional start site of the Gata4 gene. Mapping this region identified that the CCAAT-binding factor/nuclear factor-Y (CBF/NF-Y) binding to the CCAAT box was inhibited by DNR in HL-1 cardiac muscle cells and in perfused isolated mouse hearts. The DNR action on the Gata4 promoter was found to be dependent on p53, since DNR promoted nuclear binding of p53 to CBF/NF-Y and pifithrin-α (a p53 inhibitor) attenuated DNR down-regulation of GATA4.
  
  
  CONCLUSIONS
  Anthracycline down-regulation of GATA4 is mediated by the inhibition of Gata4 gene transcription via a novel mechanism that involves the p53-dependent inhibition of CBF/NF-Y binding to the CCAAT box within the Gata4 promoter.
authors.affiliation: Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Ah-Mee
authors.initials: AM
authors.lastname: Park
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nagase
authors.forename: Lingling
authors.initials: L
authors.lastname: Liu
authors.forename: Shilpashree
authors.initials: S
authors.lastname: Vinod Kumar
authors.forename: Nava
authors.initials: N
authors.lastname: Szwergold
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Wong
authors.forename: Yuichiro J
authors.initials: YJ
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001483:Base Sequence; D052160:Benzothiazoles / Q000494:pharmacology; D001665:Binding Sites; D023081:CCAAT-Binding Factor / Q000378:metabolism; D002460:Cell Line; D003630:Daunorubicin / Q000633:toxicity*; D015536:Down-Regulation; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010477:Perfusion; D011401:Promoter Regions, Genetic / Q000187:drug effects; D013997:Time Factors; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D052160:Benzothiazoles; D023081:CCAAT-Binding Factor; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D016159:Tumor Suppressor Protein p53; C402244:nuclear factor Y; D014050:Toluene; C121565:pifithrin; D003630:Daunorubicin