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  Control of p21Cip by BRAP is critical for cardiomyocyte cell cycle progression and survival.

Volland, C., Schott, P., Didié, M., Männer, J., Unsöld, B., Toischer, K., et al. (2019). Control of p21Cip by BRAP is critical for cardiomyocyte cell cycle progression and survival. Cardiovascular Research, (in press). doi:10.1093/cvr/cvz177.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-3EDA-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-AF8A-C
Genre: Journal Article

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 Creators:
Volland, C., Author
Schott, P., Author
Didié, M., Author
Männer, J., Author
Unsöld, B., Author
Toischer, K., Author
Schmidt, C.1, Author              
Urlaub, H.1, Author              
Nickels, K., Author
Knöll, R., Author
Schmidt, A., Author
Guan, K., Author
Hasenfuß, G., Author
Seidler, T., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

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Free keywords: BRAP; cardiac development; cardiomyocyte proliferation; cell cycle; knockout mice; p21Cip
 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 signaling 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.

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Language(s): eng - English
 Dates: 2019-07-09
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1093/cvr/cvz177
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Title: Cardiovascular Research
Source Genre: Journal
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