title: Dyrk1a regulates the cardiomyocyte cell cycle via D-cyclin-dependent Rb/E2f-signalling.
abstract: Down syndrome-associated dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) is a ubiquitously expressed protein kinase. Up to date a variety of targets have been identified, establishing a key role for Dyrk1a in selected signalling pathways. In cardiomyocytes, Dyrk1a acts as a negative regulator of hypertrophy by phosphorylating transcription factors of the NFAT family, but its mechanistic function in the heart remains poorly understood. This study was designed to investigate a potential protective role of Dyrk1a in cardiac hypertrophy in vivo.
  
  
  
  We generated transgenic mice with cardiac-specific overexpression of Dyrk1a. Counterintuitively, these mice developed severe dilated cardiomyopathy associated with congestive heart failure and premature death. In search for the cause of this unexpected phenotype, we found that Dyrk1a interacts with all members of the D-cyclin family and represses their protein levels in vitro and in vivo. Particularly, forced expression of Dyrk1a leads to increased phosphorylation of Ccnd2 on Thr280 and promotes its subsequent proteasomal degradation. Accordingly, cardiomyocytes overexpressing Dyrk1a display hypo-phosphorylated Rb1, suppression of Rb/E2f-signalling, and reduced expression of E2f-target genes, which ultimately results in impaired cell cycle progression.
  
  
  
  We identified Dyrk1a as a novel negative regulator of D-cyclin-mediated Rb/E2f-signalling. As dysregulation of this pathway with impaired cardiomyocyte proliferation leads to cardiomyopathy, dose-specific Dyrk1a expression and activity appears to be critical for the hyperplastic and hypertrophic growth of the developing heart.
authors.affiliation: Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3 (Building 6), 24105 Kiel, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hille
authors.affiliation: Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3 (Building 6), 24105 Kiel, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Dierck
authors.affiliation: Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3 (Building 6), 24105 Kiel, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: Kühl
authors.affiliation: Institute of Immunology, Christian-Albrechts-University Kiel, UKSH Campus Kiel, 24105 Kiel, Germany.
authors.forename: Justyna
authors.initials: J
authors.lastname: Sosna
authors.affiliation: Institute of Immunology, Christian-Albrechts-University Kiel, UKSH Campus Kiel, 24105 Kiel, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Adam-Klages
authors.affiliation: Institute of Immunology, Christian-Albrechts-University Kiel, UKSH Campus Kiel, 24105 Kiel, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Adam
authors.affiliation: Institute of Anatomy, Christian-Albrechts-University Kiel, 24118 Kiel, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.affiliation: Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3 (Building 6), 24105 Kiel, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany norbert.frey@uksh.de christian.kuhn@uksh.de.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.affiliation: Department of Internal Medicine III, University Medical Center of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3 (Building 6), 24105 Kiel, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany norbert.frey@uksh.de christian.kuhn@uksh.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Kuhn
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002453:Cell Cycle; D049109:Cell Proliferation; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D050684:E2F Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017208:Rats, Wistar; D012175:Retinoblastoma / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D000097603:Dyrk Kinases
chemical_list: D056741:Cyclin D; D050684:E2F Transcription Factors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases
keywords: Cell cycle; Dyrk1a; Heart failure; Hypertrophy; Rb/E2f-signalling