Abstract 17301: DYRK1A Overexpression Leads to Severe Cardiomyopathy via Altered Cyclin D-Dependent Rb/E2f-Signaling
Down syndrome-associated dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (Dyrk1a) is ubiquitously expressed and involved in multiple signaling pathways. In neonatal rat ventricular cardiomyocytes (NRVCMs) overexpression of Dyrk1a antagonizes hypertrophy in response to various stimuli, whereas an inducible transgenic mouse model surprisingly lacks any antihypertrophic effects.
In order to further unravel the role of Dyrk1a in cardiac hypertrophy and heart failure we performed a yeast two-hybrid screen, identified and confirmed cyclin D2 (Ccnd2) as a novel interaction partner of Dyrk1a. D-cyclins are regulators of cell cycle progression by mediating S phase entry. They activate cyclin-dependent protein kinases (Cdks) to hyperphosphorylate pocket proteins of the Retinoblastoma family (Rbs), which in turn release bound E2f transcription factors. All three D-cyclins are upregulated in hypertrophic growth. We here show that under baseline conditions as well as in a model of endothelin-1 induced hypertrophy, Dyrk1a significantly reduces protein levels of cyclin D1, cyclin D2 and cyclin D3. Accordingly, NRVCMs overexpressing Dyrk1a display hypophosphorylated Rb1 and strong suppression of Rb/E2f-signaling as confirmed by an E2f-dependent luciferase-reporter and reduced expression of E2f-controlled genes, including activators E2f1, E2f2 and E2f3a.
In order to test the relevance of this new pathway in vivo, we next created transgenic mice expressing Dyrk1a under the regulation of the alpha cardiac myosin heavy chain promoter. These mice develop severe dilated cardiomyopathy (DCM) and die prematurely as a result of congestive heart failure. Data from different transgenic lines suggest that DCM progression correlates with Dyrk1a-overexpression levels and is associated with dysregulation of Rb/E2f controlled genes.
In summary we identified Dyrk1a as a novel negative regulator of D-cyclin mediated Rb/E2f-signaling. As dysregulation of this pathway leads to cardiomyopathy, Dyrk1a expression and activity appears to be critical for hypertrophic growth and cell cycle progression of cardiomyocytes, in particular in the context of the developing heart.
- © 2013 by American Heart Association, Inc.