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  • 1
    In: Cardiovascular Research, 2010, Vol. 86(1), pp.92-102
    Description: AIMS: Although the fundamental role of the E2F transcription factor family in cell proliferation is well established, the specific function of E2F4 is unclear. On the basis of findings from cell culture experiments, E2F4 is generally considered as an inhibitor of cell proliferation. Accumulating evidence suggests, however, that E2F4 acts as an activator of cell proliferation in certain contexts. Here, we have investigated the role of E2F4 during heart development and in proliferating cardiomyocytes.METHODS AND RESULTS: Nuclear E2F4 expression in cardiomyocytes declined during mouse heart development, which correlates with the loss of proliferative capacity of cardiomyocytes. Re-induction of proliferation in postnatal cardiomyocytes increased nuclear E2F4 expression. E2F4 accumulated in the nucleus at the end of the S phase, remained nuclear during mitosis, and disappeared at the end of cytokinesis. siRNA-mediated inhibition of E2F4 in proliferating postnatal cardiomyocytes resulted in a significant reduction in mitosis, but not in DNA synthesis. Co-staining of E2F4 and Crest revealed that E2F4 co-localizes with kinetochores. Moreover, chromatin immunoprecipitation showed that E2F4 binds to centromeric alpha-satellite DNA during mitosis.CONCLUSION: Our data indicate that E2F4 is required for cardiomyocyte proliferation and suggest a function for E2F4 in mitosis.
    Keywords: E2f4 ; Cell Cycle ; Cardiomyocyte Proliferation ; Kinetochore
    ISSN: 0008-6363
    E-ISSN: 1755-3245
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  • 2
    In: Cardiovascular Research, 2010, Vol. 85(4), pp.681-690
    Description: AIMS: Proliferation of mammalian cardiomyocytes stops during the first weeks after birth, preventing the heart from regenerating after injury. Recently, several studies have indicated that induction of cardiomyocyte proliferation can be utilized to regenerate the mammalian heart. Thus, it is important to identify novel factors that can induce proliferation of cardiomyocytes. Here, we determine the effect of TNF-related weak inducer of apoptosis (TWEAK) on cardiomyocytes, a cytokine known to regulate proliferation in several other cell types.METHODS AND RESULTS: Stimulation of neonatal rat cardiomyocytes with TWEAK resulted in increased DNA synthesis, increased expression of the proliferative markers Cyclin D2 and Ki67, and downregulation of the cell cycle inhibitor p27KIP1. Importantly, TWEAK stimulation resulted also in mitosis (H3P), cytokinesis (Aurora B), and increased cardiomyocyte numbers. Loss of function experiments revealed that re-induction of proliferation was dependent on tumour necrosis factor receptor superfamily member 12A (FN14) signalling. Downstream signalling was mediated through activation of extracellular signal-regulated kinases and phosphatidylinositol 3-kinase as well as inhibition of glycogen synthase kinase-3beta. In contrast to neonatal cardiomyocytes, TWEAK had no effect on adult rat cardiomyocytes due to developmental downregulation of its receptor FN14. However, adenoviral expression of FN14 enabled efficient induction of cell cycle re-entry in adult cardiomyocytes after TWEAK stimulation.CONCLUSION: Our data establish TWEAK as a positive regulator of cardiomyocyte proliferation.
    Keywords: Tweak ; Fn14 ; Heart ; Cardiomyocytes ; Proliferation ; Signalling
    ISSN: 0008-6363
    E-ISSN: 1755-3245
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