Volland, Cornelia and Schott, Peter and Didie, Michael and Maenner, Joerg and Unsoeld, Bernhard and Toischer, Karl and Schmidt, Carla and Urlaub, Henning and Nickels, Katrin and Knoell, Ralph and Schmidt, Albrecht and Guan, Kaomei and Hasenfuss, Gerd and Seidler, Tim (2020) Control of p21(Cip) by BRCA1-associated protein is critical for cardiomyocyte cell cycle progression and survival. CARDIOVASCULAR RESEARCH, 116 (3). pp. 592-604. ISSN 0008-6363, 1755-3245
Full text not available from this repository. (Request a copy)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 p21(Cip). 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. alpha MHC-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 3weeks 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 p21(Cip) which we identify as the link between BRAP and cell cycle/apoptosis. BRAP deletion enhanced p21(Cip) expression, while BRAP overexpression in cardiomyocyte-specific transgenic mice impeded p21(Cip) expression. That was paralleled by enhanced nuclear Ki-67 expression and DNA synthesis. Conclusion By controlling p21(Cip) activity BRAP expression controls cell cycle activity and prevents developmental arrest in developing cardiomyocytes and apoptosis in adult cardiomyocytes.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DNA-SYNTHESIS; HEART; BRAP; PROLIFERATION; ARREST; ADULT; RISK; IDENTIFICATION; HYPERTROPHY; TRANSITION; BRAP; Cell cycle; p21(Cip); Cardiomyocyte proliferation; Cardiac development; Knockout mice |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Mar 2021 05:48 |
| Last Modified: | 30 Mar 2021 05:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/45030 |
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