Control of p21Cip by BRCA1-associated protein is critical for cardiomyocyte cell cycle progression and survival

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Cornelia Volland - , Georg-August-Universität Göttingen (Autor:in)
  • Peter Schott - , Georg-August-Universität Göttingen, Klinikum Werra-Meißner GmbH (Autor:in)
  • Michael Didié - , Georg-August-Universität Göttingen, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Jörg Männer - , Georg-August-Universität Göttingen (Autor:in)
  • Bernhard Unsöld - , Georg-August-Universität Göttingen, Universität Regensburg (Autor:in)
  • Karl Toischer - , Georg-August-Universität Göttingen, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Carla Schmidt - , Max Planck Institute for Biophysical Chemistry (Karl Friedrich Bonhoeffer Institute), Martin-Luther-Universität Halle-Wittenberg (Autor:in)
  • Henning Urlaub - , Max Planck Institute for Biophysical Chemistry (Karl Friedrich Bonhoeffer Institute), Georg-August-Universität Göttingen (Autor:in)
  • Katrin Nickels - , Universitätsmedizin Göttingen, Siemens AG, AstraZeneca (Autor:in)
  • Ralph Knöll - , Universitätsmedizin Göttingen, Karolinska Institutet, Medizinische Universität Graz (Autor:in)
  • Albrecht Schmidt - , Georg-August-Universität Göttingen, Technische Universität Dresden (Autor:in)
  • Kaomei Guan - , Institut für Pharmakologie und Toxikologie, Universitätsmedizin Göttingen, Georg-August-Universität Göttingen (Autor:in)
  • Gerd Hasenfuß - , Georg-August-Universität Göttingen, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)
  • Tim Seidler - , Georg-August-Universität Göttingen, Deutsches Zentrum für Herz-Kreislaufforschung (DZHK) (Autor:in)

Abstract

Aims: Identifying the key components in cardiomyocyte cell cycle regulation is of relevance for the understanding of cardiac development and adaptive and maladaptive processes in the adult myocardium. BRCA1-associated protein (BRAP) has been suggested as a cytoplasmic retention factor for several proteins including Cyclin-dependent-kinase inhibitor p21Cip. We observed profound expressional changes of BRAP in early postnatal myocardium and investigated the impact of BRAP on cardiomyocyte cell cycle regulation. Methods and results: General knockout of Brap in mice evoked embryonic lethality associated with reduced myocardial wall thickness and lethal cardiac congestion suggesting a prominent role for BRAP in cardiomyocyte proliferation. αMHC-Cre driven cardiomyocyte-specific knockout of Brap also evoked lethal cardiac failure shortly after birth. Likewise, conditional cardiomyocyte-specific Brap deletion using tamoxifen-induced knockout in adult mice resulted in marked ventricular dilatation and heart failure 3 weeks after induction. Several lines of evidence suggest that Brap deletion evoked marked inhibition of DNA synthesis and cell cycle progression. In cardiomyocytes with proliferative capacity, this causes developmental arrest, whereas in adult hearts loss of BRAP-induced apoptosis. This is explained by altered signalling through p21Cip which we identify as the link between BRAP and cell cycle/apoptosis. BRAP deletion enhanced p21Cip expression, while BRAP overexpression in cardiomyocyte-specific transgenic mice impeded p21Cip expression. That was paralleled by enhanced nuclear Ki-67 expression and DNA synthesis. Conclusion: By controlling p21Cip activity BRAP expression controls cell cycle activity and prevents developmental arrest in developing cardiomyocytes and apoptosis in adult cardiomyocytes.

Details

OriginalspracheEnglisch
Seiten (von - bis)592-604
Seitenumfang13
FachzeitschriftCardiovascular research
Jahrgang116
Ausgabenummer3
PublikationsstatusVeröffentlicht - 1 März 2020
Peer-Review-StatusJa

Externe IDs

PubMed 31286143

Schlagworte

Schlagwörter

  • BRAP, Cardiac development, Cardiomyocyte proliferation, Cell cycle, Knockout mice, p21