| First Author | Weiss CS | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 9 | Pages | e70848 |
| PubMed ID | 24023715 | Mgi Jnum | J:206403 |
| Mgi Id | MGI:5550194 | Doi | 10.1371/journal.pone.0070848 |
| Citation | Weiss CS, et al. (2013) DYRK2 negatively regulates cardiomyocyte growth by mediating repressor function of GSK-3beta on eIF2Bepsilon. PLoS One 8(9):e70848 |
| abstractText | BACKGROUND: A prerequisite of hypertrophic response of the myocardium is an increase in protein synthesis. A central regulator of translation initiation is Eukaryotic initiation factor 2B (eIF2B). Here we assessed the hypothesis that regulation of protein synthesis via eIF2Bepsilon is essential to cardiac hypertrophic response in vivo. METHODS: Two transgenic mouse lines were generated with cardiac restricted overexpression of eIF2Bepsilon or its mutant eIF2Bepsilon-eIFS(535)A, which cannot be inactivated by phosphorylation through GSK-3beta. RESULTS: (1) Under baseline conditions eIF2Bepsilon transgenic mice showed no difference in cardiac phenotype compared to wild type, whereas in the mutant eIF2Bepsilon-S(535)A an increase in LV/tibia length (7.5 +/- 0.4 mg/mm vs. 6.2 +/- 0.2 mg/mm, p<0.001) and cardiomyocyte cross sectional area (13004 +/- 570 vs. 10843 +/- 347 RU, p<0.01) was observed. (2) Cardiac overexpression of eIF2Bepsilon did not change the response of the heart to pathologic stress induced by chronic isoproterenol treatment. (3) Cardiac overexpression of the eIF2Bepsilon transgene was followed by overexpression of DYRK2 which is known to prime the inhibitory action of GSK-3beta on eIF2Bepsilon, while DYRK1A and GSK-3beta itself were not increased. (4) In C57BL/6 mice after 48 h of isoproterenol-stimulation or aortic banding, eIF2Bepsilon was increased and DYRK2 was concomitantly decreased. (5) In line with these in vivo findings, siRNA knockdown of DYRK2 in cultured cardiomyocytes resulted in decreased levels of p(S535)- eIF2Bepsilon, (6) whereas adenoviral induced overexpression of DYRK2 was accompanied by clearly increased phosphorylation of eIF2Bepsilon, indicating a coordinated response pattern (7) Adenoviral induced overexpression of DYRK2 leads to significantly reduced cardiomyocyte size and diminishes hypertrophic response to adrenergic stimulation. CONCLUSIONS: The interaction of GSK-3beta and its priming kinase DYRK2 regulate the activity of eIF2Bepsilon in cardiac myocytes. DYRK2 is a novel negative regulator of cardiomyocyte growth. DYRK2 could serve as a therapeutic option to regulate myocardial growth. |
