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ErbB4 localization to cardiac myocyte nuclei, and its role in myocyte DNA damage response

Basak Icli1, Ajit Bharti, Laura Pentassuglia

  • 1Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Biochemical and Biophysical Research Communications
|January 17, 2012
PubMed

Insights

Full-length ErbB4 receptor tyrosine kinase translocates to the nucleus of cardiac myocytes, regulating the DNA damage response. This nuclear localization of ErbB4 is crucial for p53 and p21 regulation following doxorubicin treatment.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cell Biology

Background:

  • ErbB4 receptor tyrosine kinase intracellular domain translocates to the nucleus, regulating p53.
  • The role of ErbB4 in cardiac myocytes and its nuclear localization is not well understood.

Purpose of the Study:

  • To investigate if ErbB4 localizes to the nucleus of adult rat ventricular myocytes (ARVM).
  • To determine if ErbB4 regulates p53 transcriptional activity in ARVM.

Main Methods:

  • Immunofluorescence to confirm nuclear localization of full-length ErbB4 in ARVM.
  • Western blotting to analyze p53 and p21 expression.
  • Doxorubicin treatment to induce DNA damage response.
  • Inhibition of ErbB4 kinase activity with AG1478.
  • Suppression of ErbB4 expression using small interfering RNA (siRNA).

Main Results:

  • Full-length ErbB4 was found to localize in the nucleus of ARVM.
  • Nuclear localization of ErbB4 did not require Protein Kinase C or γ-secretase activity.
  • Only the non-cleavable JM-b isoform of ErbB4 was expressed in ARVM.
  • Doxorubicin-induced p53 and p21 expression was suppressed by AG1478 or ErbB4 siRNA.
  • ErbB4 plays a role in the DNA damage response in cardiac myocytes.

Conclusions:

  • ErbB4 localizes to the nucleus of cardiac myocytes as a full-length protein.
  • ErbB4 plays a significant role in the DNA damage response pathway in cardiac myocytes, specifically in regulating p53 and p21.
  • The non-cleavable JM-b isoform of ErbB4 is responsible for these nuclear functions in ARVM.

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