title: ErbB4 localization to cardiac myocyte nuclei, and its role in myocyte DNA damage response.
abstract: The intracellular domain of ErbB4 receptor tyrosine kinase is known to translocate to the nucleus of cells where it can regulate p53 transcriptional activity. The purpose of this study was to examine whether ErbB4 can localize to the nucleus of adult rat ventricular myocytes (ARVM), and regulate p53 in these cells. We demonstrate that ErbB4 does locate to the nucleus of cardiac myocytes as a full-length protein, although nuclear location occurs as a full-length protein that does not require Protein Kinase C or γ-secretase activity. Consistent with this we found that only the non-cleavable JM-b isoform of ErbB4 is expressed in ARVM. Doxorubicin was used to examine ErbB4 role in regulation of a DNA damage response in ARVM. Doxorubicin induced p53 and p21 was suppressed by treatment with AG1478, an EGFR and ErbB4 kinase inhibitor, or suppression of ErbB4 expression with small interfering RNA. Thus ErbB4 localizes to the nucleus as a full-length protein, and plays a role in the DNA damage response induced by doxorubicin in cardiac myocytes.
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Basak
authors.initials: B
authors.lastname: Icli
authors.forename: Ajit
authors.initials: A
authors.lastname: Bharti
authors.forename: Laura
authors.initials: L
authors.lastname: Pentassuglia
authors.forename: Xuyang
authors.initials: X
authors.lastname: Peng
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D066247:Receptor, ErbB-4; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D016159:Tumor Suppressor Protein p53; D020032:Tyrphostins; C101044:RTKI cpd; D004317:Doxorubicin; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4